Central nervous system(CNS) axons fail to regenerate following brain or spinal cord injury(SCI),which typically leads to permanent neurological deficits.Peripheral nervous system axons,howeve r,can regenerate followin...Central nervous system(CNS) axons fail to regenerate following brain or spinal cord injury(SCI),which typically leads to permanent neurological deficits.Peripheral nervous system axons,howeve r,can regenerate following injury.Understanding the mechanisms that underlie this difference is key to developing treatments for CNS neurological diseases and injuries characterized by axonal damage.To initiate repair after peripheral nerve injury,dorsal root ganglion(DRG) neurons mobilize a pro-regenerative gene expression program,which facilitates axon outgrowth.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is notorious for its aggressive progression and dismal prognosis,with chromatin accessibility dynamics emerging as pivotal yet poorly understood drivers.AIM To dissect how multi...BACKGROUND Hepatocellular carcinoma(HCC)is notorious for its aggressive progression and dismal prognosis,with chromatin accessibility dynamics emerging as pivotal yet poorly understood drivers.AIM To dissect how multilayered chromatin regulation sustains oncogenic transcription and tumor-stroma crosstalk in HCC,we combined multiomics single cell analysis.METHODS We integrated single-cell RNA sequencing and paired single-cell assay for transposase-accessible chromatin with sequencing data of HCC samples,complemented by bulk RNA sequencing validation across The Cancer Genome Atlas,Liver Cancer Institute,and GSE25907 cohorts.Cell type-specific chromatin architectures were resolved via ArchR,with regulatory hubs identified through peak-to-gene linkages and coaccessibility networks.Functional validation employed A485-mediated histone 3 lysine 27 acetylation suppression and small interfering RNA targeting DGAT1.RESULTS Malignant hepatocytes exhibited expanded chromatin accessibility profiles,characterized by increased numbers of accessible peaks and larger physical regions despite reduced peak intensity.Enhancer-like peaks enriched in malignant regulation,forming long-range hubs.Eighteen enhancer-like peak-related genes showed tumor-specific overexpression and diagnostic accuracy,correlating with poor prognosis.Intercellular coaccessibility analysis revealed tumor-stroma symbiosis via shared chromatin states.Pharmacological histone 3 lysine 27 acetylation inhibition paradoxically downregulated DGAT1,the hub gene most strongly regulated by chromatin accessibility.DGAT1 knockdown suppressed cell proliferation.CONCLUSION Multilayered chromatin reprogramming sustains HCC progression through tumor-stroma crosstalk and DGAT1-related oncogenic transcription,defining targetable epigenetic vulnerabilities.展开更多
Meiotic resumption in mammalian oocytes involves nuclear and organelle structural changes,notably the chromatin configuration transition from a non-surrounding nucleolus(NSN)to surrounding nucleolus(SN)in germinal ves...Meiotic resumption in mammalian oocytes involves nuclear and organelle structural changes,notably the chromatin configuration transition from a non-surrounding nucleolus(NSN)to surrounding nucleolus(SN)in germinal vesicle oocytes.In the current study,we found that nuclear speckles(NSs),a subnuclear structure mainly composed of serine-arginine(SR)proteins,changed from a diffuse spotted distribution in mouse NSN oocytes to an aggregated pattern in SN oocytes.We also found that the SR protein-specific kinase 1(SRPK1),an enzyme that phosphorylates SR proteins,co-localized with NSs at the SN stage,and that NSN oocytes failed to transition to SN oocytes after the inhibition of SRPK1 activity.Furthermore,the typical structure of the chromatin ring around the nucleolus in SN oocytes collapsed after treatment with an SRPK1 inhibitor.Mechanistically,phosphorylated SR proteins were found to be related to chromatin as shown by a salt extraction experiment,and in situ DNaseⅠassay showed that the accessibility of chromatin was enhanced in SN oocytes when SRPK1 was inhibited,accompanied by a decreased repressive modification on histone and the abnormal recurrence of a transcriptional signal.In conclusion,our results indicated that SRPK1-regulated phosphorylation of SR proteins was involved in the NSN-SN transition and played an important role in maintaining the condensed nucleus of SN oocytes via interacting with chromatin.展开更多
Temperature fluctuations challenge ectothermic species,particularly tropical fish dependent on external temperatures for physiological regulation.However,the molecular mechanisms through which low-temperature stress i...Temperature fluctuations challenge ectothermic species,particularly tropical fish dependent on external temperatures for physiological regulation.However,the molecular mechanisms through which low-temperature stress impacts immune responses in these species,especially in relation to chromatin accessibility and epigenetic regulation,remain poorly understood.In this study,we investigate chromatin and transcriptional changes in the head kidney and thymus tissues of Nile tilapia(Oreochromis niloticus),a tropical fish of significant economic importance,under cold stress.By analyzing cis-regulatory elements in open chromatin regions and their associated transcription factors(TFs),we construct a comprehensive transcriptional regulatory network(TRN)governing immune responses,including DNA damage-induced apoptosis.Our analysis identifies 119 TFs within the TRN,with Stat1 emerging as a central hub exhibiting distinct binding dynamics under cold stress,as revealed by footprint analysis.Overexpression of Stat1 in immune cells leads to apoptosis and increases the expression of apoptosis-related genes,many of which contain Stat1-binding sites in their regulatory regions,emphasizing its critical role in immune cell survival during cold stress.These results provide insights into the transcriptional and epigenetic regulation of immune responses to cold stress in tilapia and highlight Stat1 as a promising target for enhancing cold tolerance in tropical fish species.展开更多
The insect fat body is comparable to the liver and adipose tissue in vertebrates,and plays a pivotal role in energy metabolism,nutrient storage,and reproduction.During metamorphosis,the fat body is disassembled via pr...The insect fat body is comparable to the liver and adipose tissue in vertebrates,and plays a pivotal role in energy metabolism,nutrient storage,and reproduction.During metamorphosis,the fat body is disassembled via programmed cell death and cell dissociation.After adult eclosion,the fat body is reconstructed either by repopulation from the remaining juvenile fat body cells or by differentiation from adult progenitor cells.This reconstruction is a prerequisite for initiating the extensive synthesis of vitellogenin(Vg),which is necessary for the maturation of eggs.Despite its significance,the underlying mechanisms of this reconstruction remain inadequately understood.Transcriptome analysis of the fat bodies from migratory locusts at 0-5 days post adult emergence revealed 79 genes associated with chromatin remodeling.Weighted gene co-expression network analysis indicated a positive correlation between chromatin remodeling and fat body reconstitution.Protein-protein interaction analysis revealed that brahma,which encodes the catalytic subunit of the SWI/SNF chromatin remodeling complex,is crucial for post-adult-eclosion fat body development.qRT-PCR analysis demonstrated that the levels of brahma mRNA in the fat body are progressively increased during the previtellogenic stage,then reach the peak and remain elevated in the vitellogenic phase.Furthermore,brahma is expressed in response to gonadotropic juvenile hormone(JH).Knockdown of brahma led to a marked reduction in Vg expression within the fat body,along with arrested ovarian growth.These findings shed light on the involvement of brahmamediated chromatin remodeling in JH-stimulated fat body reconstruction and reproduction of adult female locusts.展开更多
Objective:To evaluate how DNA fragmentation index(DFI)and chromatin denaturation index(CDI)relate to semen parameters across different types of male infertility,thereby improving the understanding and assessment of sp...Objective:To evaluate how DNA fragmentation index(DFI)and chromatin denaturation index(CDI)relate to semen parameters across different types of male infertility,thereby improving the understanding and assessment of sperm quality.Methods:A prospective and descriptive cohort study was conducted over two years at the Integrated Physiology Laboratory of the University of Carthage in collaboration with the Alyssa Fertility Group,Tunisia.A total of 163 participants were classified into five groups based on their semen parameters:normozoospermia,oligozoospermia,asthenozoospermia,teratozoospermia,and oligoastheno-teratozoospermia.The normozoospermia group was selected from volunteers who had children.Semen samples were analyzed according to WHO guidelines.DFI was measured using Halosperm®and CDI was tested using aniline blue staining.Results:Both DFI and CDI were significantly higher in all infertility groups,with the oligozoospermia group showing the highest DFI and CDI.Negative correlations were found between DFI/CDI and sperm motility,concentration,and morphology in the affected groups.The normozoospermia group served as a control with the lowest DFI and CDI values.Conclusions:DFI and CDI are increasingly recognized as important biomarkers for evaluating sperm quality in cases of male infertility.Their elevated levels in patients with oligozoospermia,asthenozoospermia,teratozoospermia,and oligo-asthenoteratozoospermia underscore their potential role in not only diagnosing male infertility but also in assessing the overall reproductive outcomes for affected individuals,thus guiding more effective treatment strategies.展开更多
Rice(Oryza sativa)is a staple food for more than half of the world's population and a critical crop for global agriculture.Understanding the regulatory mechanisms that control gene expression in the rice genome is...Rice(Oryza sativa)is a staple food for more than half of the world's population and a critical crop for global agriculture.Understanding the regulatory mechanisms that control gene expression in the rice genome is fundamental for advancing agricultural productivity and food security.In mechanism,cis-regulatory elements(including promoters,enhancers,silencers,and insulators)are key DNA sequences whose activities determine the spatial and temporal expression patterns of nearby genes(Yocca and Edger,2022;Schmitz et al.,2022).展开更多
Total or severe teratospermia affects the prognosis of fertility and causes serious problems for patients undergoing assisted reproduction[1].The pathophysiological mechanism of teratospermia is unclear.It has been sh...Total or severe teratospermia affects the prognosis of fertility and causes serious problems for patients undergoing assisted reproduction[1].The pathophysiological mechanism of teratospermia is unclear.It has been shown that patients with sperm parameters abnormalities and abnormal morphology have a high rate of fragmentation and sperm DNA decondensation[2,3],and that sperm DNA fragmentation analysis could be used as a predictor factor of fertility potential[4].展开更多
During cellular proliferation DNA undergoes frequent rep-lication cycles in which errors inevitably accumulate.DNA simultaneously faces continuous damage from endogenous sources[e.g.,reactive oxygen species(ROS)]and e...During cellular proliferation DNA undergoes frequent rep-lication cycles in which errors inevitably accumulate.DNA simultaneously faces continuous damage from endogenous sources[e.g.,reactive oxygen species(ROS)]and environmen-tal stressors,such as ultraviolet(UV)and ionizing radiation(IR).Such lesions compromise genomic stability and may escalate into DNA double-strand breaks(DSBs).Failure to repair DSBs can ultimately trigger cell death1.展开更多
Ribosomal RNA(rRNA)synthesis is intricately tied to cellular growth and proliferation.Basic fibroblast growth factor(FGF2),a pivotal factor for bone marrow mesenchymal stem cells(BMSCs),can stimulates rRNA transcripti...Ribosomal RNA(rRNA)synthesis is intricately tied to cellular growth and proliferation.Basic fibroblast growth factor(FGF2),a pivotal factor for bone marrow mesenchymal stem cells(BMSCs),can stimulates rRNA transcription,though the underlying mechanism remains unknown.Here,we demonstrate that the cytoplasm-nucleus translocation of FGF2 is determined by the stable nuclear localization motif.Meanwhile,the nuclear FGF2 regulates rRNA expression and BMSCs proliferation via phase separation.Next,through FGF2 related epigenomics and 3D genomes analysis,we identified chromatin architectures during BMSCs differentiation and aging.In the process,topologically associating domains(TADs)and chromatin loops profiling revealed the attenuated genomic interaction among proximal chromosomes 13,14,15,21,and 22,where phase-separated FGF2 facilitates rDNA transcription depend on specific super-enhancers(SEs).Furthermore,we validated that FGF2 orchestrates rDNA chromatin architecture in coordination with STAT5.Together,these findings underscore the pivotal role of FGF2 in rDNA chromatin architectures,which determines BMSCs cell fate.展开更多
Wiedemann-Steiner syndrome(OMIM#605130)is a rare congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature;consistent facial features,including long eyelashes,thick or arche...Wiedemann-Steiner syndrome(OMIM#605130)is a rare congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature;consistent facial features,including long eyelashes,thick or arched eyebrows with a lateral flare,wide nasal bridge,and downslanting and vertically narrow palpebral fissures;mild to moderate intellectual disability;behavioral difficulties;and hypertrichosis on the back.It is caused by heterozygous pathogenic variants in KMT2A.This gene has an established role in histone methylation,which explains the overlap of Wiedemann-Steiner syndrome with other chromatinopathies,a heterogeneous group of syndromic conditions that share a common trigger:The disruption of one of the genes involved in chromatin modification,leading to dysfunction of the epigenetic machinery.展开更多
The eukaryotic genome is organized into functionally and structurally distinct domains, representing regulatory unitsfor gene expression and chromosome behavior. DNA sequences that mark the border between adjacent dom...The eukaryotic genome is organized into functionally and structurally distinct domains, representing regulatory unitsfor gene expression and chromosome behavior. DNA sequences that mark the border between adjacent domains are theinsulators or boundary elements, which are required in maintenance of the function of different domains. Some insula-tors need others enable to play insulation activity. Chromatin domains are defined by distinct sets of post-translationallymodified histones. Recent studies show that these histone modifications are also involved in establishment of sharpchromatin boundaries in order to prevent the spreading of distinct domains. Additionally, in some loci, the high-orderchromatin structures for long-range looping interactions also have boundary activities, suggesting a correlation betweeninsulators and chromatin loop domains. In this review, we will discuss recent progress in the field of chromatin domainboundaries.展开更多
Diagnosis of male infertility has mainly been based on the World Health Organization （WHO） manual-based semen parameter＇s concentration, motility and morphology. It has, however, become apparent that none of these ...Diagnosis of male infertility has mainly been based on the World Health Organization （WHO） manual-based semen parameter＇s concentration, motility and morphology. It has, however, become apparent that none of these parameters are reliable markers for evaluation of the fertility potential of a couple. A search for better markers has led to an increased focus on sperm chromatin integrity testing in fertility work-up and assisted reproductive techniques. During the last couple of decades, numerous sperm DNA integrity tests have been developed. These are claimed to be characterized by a lower intraindividual variation, less intralaboratory and interlaboratory variation and thus less subjective than the conventional sperm analysis. However, not all the sperm chromatin integrity tests have yet been shown to be of clinical value. So far, the test that has been found to have the most stable clinical threshold values in relation to fertility is the sperm chromatin structure assay （SCSA）, a flow cytometric test that measures the susceptibility of sperm DNA to acid-induced DNA denaturation in situ. Sperm DNA fragmentation as measured by SCSA has shown to be an independent predictor of successful pregnancy in first pregnancy planners as well as in couples undergoing intrauterine insemination, and can be used as a tool in investigation, counseling and treatment of involuntary childlessness. More conflicting data exist regarding the role of sperm DNA fragmentation in relation to fertilization, pre-embryo development and pregnancy outcome in in vitro fertilization and intracytoplasmic sperm injection （ICSI）.展开更多
Spermiogenesis is a complex process leading to the formation of motile spermatozoa characterized by a highly stable chromatin compaction that transfers the paternal genome into the oocyte. It is commonly held that the...Spermiogenesis is a complex process leading to the formation of motile spermatozoa characterized by a highly stable chromatin compaction that transfers the paternal genome into the oocyte. It is commonly held that these haploid cells are devoid of transcriptional and translational activities and that the transcripts represent remnants of stored mRNAs. Recently, the chromatin organization of mature spermatozoa has been revisited as a double nucleoprotamine-nucleohistone structure possessing less-condensed regions sensitive to nuclease activity, which could be implicated in the expression of genes involved in the early embryo development. The existence of a complex population of mRNAs in human sperm is well-documented, but their role is not yet elucidated. Evidence for a latent transcriptional capacity and/or a potential de novo translation in mature spermatozoa from fertile men are essential for understanding the last steps of sperm maturation, such as capacitation and acrosome reaction. As such, we have documented the relationship between sperm quality and the distribution of sperm RNAs by showing divergent levels of transcripts encoding for proteins involved in either nuclear condensation （protamines 1 and 2） or in capacitation （eNOS and nNOS, c-myc） or in motility and sperm survival （aromatase） between low and high motile sperm issued from the same sample. Therefore, analyzing the profile of mRNAs could be helpful either as a diagnostic tool for evaluating male fertility after spermatogenesis or for prognosis use for fertilization.展开更多
The aim of this study was to investigate whether the sperm chromatin structure assay （SCSA） results after swim-up are related to fertilization rates, embryo quality and pregnancy rates following in vitrofertilizati...The aim of this study was to investigate whether the sperm chromatin structure assay （SCSA） results after swim-up are related to fertilization rates, embryo quality and pregnancy rates following in vitrofertilization （IVF）. A total of 223 couples undergoing IVF in our hospital from October 2008 to September 2009 were included in this study. Data on the IVF process and sperm chromatin structure assay results were collected. Fertilization rate, embryo quality and IVF success rates of different DNA fragmentation index （DFI） subgroups and high DNA stainability （HDS） subgroups were compared. There were no significant differences in fertilization rate, clinical pregnancy or delivery rates between the DFI and HDS subgroups. However, the group with abnormal DFI had a lower good embryo rate. So, we concluded that the SCSA variables, either DFI or HDS after swim-up preparation, were not valuable in predicting fertilization failure or pregnancy rate, but an abnormal DFI meant a lower good embryo rate following IVF.展开更多
The study of embryonic stem cells is in the spotlight in many laboratories that study the structure and function of chromatin and epigenetic processes. The key properties of embryonic stem cells are their capacity for...The study of embryonic stem cells is in the spotlight in many laboratories that study the structure and function of chromatin and epigenetic processes. The key properties of embryonic stem cells are their capacity for selfrenewal and their pluripotency. Pluripotent stem cells are able to differentiate into the cells of all three germ layers, and because of this property they represent a promising therapeutic tool in the treatment of diseases such as Parkinson's disease and diabetes, or in the healing of lesions after heart attack. As the basic nuclear unit, chromatin is responsible for the regulation of the functional status of cells, including pluripotency and differentiation. Therefore, in this review we discuss the functional changes in chromatin during differentiation and the correlation between epigenetics events and the differentiation potential of embryonic stem cells. In particular we focus on post-translational histone modification, DNA methylation and the heterochromatin protein HP1 and its unique function in mouse and human embryonic stem cells.展开更多
The classical idea about the function of the mammalian sperm chromatin is that it serves to transmit a highly protected and transcriptionally inactive paternal genome, largely condensed by protamines, to the next gene...The classical idea about the function of the mammalian sperm chromatin is that it serves to transmit a highly protected and transcriptionally inactive paternal genome, largely condensed by protamines, to the next generation. In addition, recent sperm chromatin genome-wide dissection studies indicate the presence of a differential distribution of the genes and repetitive sequences in the protamine-condensed and histone-condensed sperm chromatin domains, which could be potentially involved in regulatory roles after fertilization. Interestingly, recent proteomic studies have shown that sperm chromatin contains many additional proteins, in addition to the abundant histones and protamines, with specific modifications and chromatin affinity features which are also delivered to the oocyte. Both gene and protein signatures seem to be altered in infertile patients and, as such, are consistent with the potential involvement of the sperm chromatin landscape in early embryo development. This present work reviews the available information on the composition of the human sperm chromatin and its epigenetic potential, with a particular focus on recent results derived from high-throughput genomic and proteomic studies. As a complement, we provide experimental evidence for the detection of phosphorylations and acetylations in human protamine 1 using a mass spectrometry approach. The available data indicate that the sperm chromatin is much more complex than what it was previously thought, raising the possibility that it could also serve to transmit crucial paternal epigenetic information to the embryo.展开更多
Background:The development of skeletal muscle in pigs during the embryonic stage is precisely regulated by transcriptional mechanisms,which depend on chromatin accessibility.However,how chromatin accessibility plays a...Background:The development of skeletal muscle in pigs during the embryonic stage is precisely regulated by transcriptional mechanisms,which depend on chromatin accessibility.However,how chromatin accessibility plays a regulatory role during embryonic skeletal muscle development in pigs has not been reported.To gain insight into the landscape of chromatin accessibility and the associated genome-wide transcriptome during embryonic muscle development,we performed ATAC-seq and RNA-seq analyses of skeletal muscle from pig embryos at 45,70 and 100 days post coitus(dpc).Results:In total,21,638,35,447 and 60,181 unique regions(or peaks)were found across the embryos at 45 dpc(LW45),70 dpc(LW70)and 100 dpc(LW100),respectively.More than 91%of the peaks were annotated within−1 kb to 100 bp of transcription start sites(TSSs).First,widespread increases in specific accessible chromatin regions(ACRs)from embryos at 45 to 100 dpc suggested that the regulatory mechanisms became increasingly complicated during embryonic development.Second,the findings from integrated ATAC-seq and RNA-seq analyses showed that not only the numbers but also the intensities of ACRs could control the expression of associated genes.Moreover,the motif screening of stage-specific ACRs revealed some transcription factors that regulate muscle developmentrelated genes,such as MyoG,Mef2c,and Mef2d.Several potential transcriptional repressors,including E2F6,OTX2 and CTCF,were identified among the genes that exhibited different regulation trends between the ATAC-seq and RNA-seq data.Conclusions:This work indicates that chromatin accessibility plays an important regulatory role in the embryonic muscle development of pigs and regulates the temporal and spatial expression patterns of key genes in muscle development by influencing the binding of transcription factors.Our results contribute to a better understanding of the regulatory dynamics of genes involved in pig embryonic skeletal muscle development.展开更多
The nonrandom three-dimensional organization of chromatin plays an important role in the regulation of gene expression.However,it remains unclear whether this organization is conserved and whether it is involved in re...The nonrandom three-dimensional organization of chromatin plays an important role in the regulation of gene expression.However,it remains unclear whether this organization is conserved and whether it is involved in regulating gene expression during speciation after whole-genome duplication(WGD)in plants.In this study,high-resolution interaction maps were generated using high-throughput chromatin conformation capture(Hi-C)techniques for two poplar species,Populus euphratica and Populus alba var.pyramidalis,which diverged~14 Mya after a common WGD.We examined the similarities and differences in the hierarchical chromatin organization between the two species,including A/B compartment regions and topologically associating domains(TADs),as well as in their DNA methylation and gene expression patterns.We found that chromatin status was strongly associated with epigenetic modifications and gene transcriptional activity,yet the conservation of hierarchical chromatin organization across the two species was low.The divergence of gene expression between WGD-derived paralogs was associated with the strength of chromatin interactions,and colocalized paralogs exhibited strong similarities in epigenetic modifications and expression levels.Thus,the spatial localization of duplicated genes is highly correlated with biased expression during the diploidization process.This study provides new insights into the evolution of chromatin organization and transcriptional regulation during the speciation process of poplars after WGD.展开更多
Plant reproduction requires the coordinated development of both male and female reproductive organs.Jasmonic acid(JA)plays an essential role in stamen filament elongation.However,the mechanism by which the JA biosynth...Plant reproduction requires the coordinated development of both male and female reproductive organs.Jasmonic acid(JA)plays an essential role in stamen filament elongation.However,the mechanism by which the JA biosynthesis genes are regulated to promote stamen elongation remains unclear.Here,we show that the chromatin remodeling complex Imitation of Switch(ISWI)promotes stamen filament elongation by regulating JA biosynthesis.We show that AT-Rich Interacting Domain 5(ARID5)interacts with CHR11,CHR17,and RLT1,several known subunits of ISWI.Mutations in ARID5 and RLTs caused a reduced seed set due to greatly shortened stamen filaments.RNA-seq analyses reveal that the expression of key genes responsible for JA biosynthesis is significantly down-regulated in the arid5 and rlt mutants.Consistently,the JA levels are drastically decreased in both arid5 and rlt mutants.Chromatin immunoprecipitationquantitative PCR analyses further show that ARID5 is recruited to the chromatin of JA biosynthesis genes.Importantly,exogenous JA treatments can fully rescue the defects of stamen filament elongation in both arid5 and rlt mutants,leading to the partial recovery of fertility.Our results provide a clue how JA biosynthesisis positively regulated by the chromatin remodeling complex ISWI,thereby promoting stamen filament elongation in Arabidopsis.展开更多
基金supported by the Canada Foundation for Innovation (Project#44220)the Natural Sciences and Engineering Research Council of Canada (RGPIN-2024-03986)+3 种基金the Michael Smith Foundation for Health Research BCthe financial support of Health Canada,through the Canada Brain Research Fund,an innovative partnership between the Government of Canada (through Health Canada),Brain Canada Foundationthe Azrieli Foundationsupported by a Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship–Master’s Award。
文摘Central nervous system(CNS) axons fail to regenerate following brain or spinal cord injury(SCI),which typically leads to permanent neurological deficits.Peripheral nervous system axons,howeve r,can regenerate following injury.Understanding the mechanisms that underlie this difference is key to developing treatments for CNS neurological diseases and injuries characterized by axonal damage.To initiate repair after peripheral nerve injury,dorsal root ganglion(DRG) neurons mobilize a pro-regenerative gene expression program,which facilitates axon outgrowth.
基金Supported by the Science and Technology Planning Project of Guangzhou,No.2024A03J0102the Natural Science Foundation of Guangdong Province for Distinguished Young Scholar,No.2022B1515020024+1 种基金National Natural Science Foundation of China,No.82070574the Key Research and Development Program of Guangzhou,No.2023B03J1298.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is notorious for its aggressive progression and dismal prognosis,with chromatin accessibility dynamics emerging as pivotal yet poorly understood drivers.AIM To dissect how multilayered chromatin regulation sustains oncogenic transcription and tumor-stroma crosstalk in HCC,we combined multiomics single cell analysis.METHODS We integrated single-cell RNA sequencing and paired single-cell assay for transposase-accessible chromatin with sequencing data of HCC samples,complemented by bulk RNA sequencing validation across The Cancer Genome Atlas,Liver Cancer Institute,and GSE25907 cohorts.Cell type-specific chromatin architectures were resolved via ArchR,with regulatory hubs identified through peak-to-gene linkages and coaccessibility networks.Functional validation employed A485-mediated histone 3 lysine 27 acetylation suppression and small interfering RNA targeting DGAT1.RESULTS Malignant hepatocytes exhibited expanded chromatin accessibility profiles,characterized by increased numbers of accessible peaks and larger physical regions despite reduced peak intensity.Enhancer-like peaks enriched in malignant regulation,forming long-range hubs.Eighteen enhancer-like peak-related genes showed tumor-specific overexpression and diagnostic accuracy,correlating with poor prognosis.Intercellular coaccessibility analysis revealed tumor-stroma symbiosis via shared chromatin states.Pharmacological histone 3 lysine 27 acetylation inhibition paradoxically downregulated DGAT1,the hub gene most strongly regulated by chromatin accessibility.DGAT1 knockdown suppressed cell proliferation.CONCLUSION Multilayered chromatin reprogramming sustains HCC progression through tumor-stroma crosstalk and DGAT1-related oncogenic transcription,defining targetable epigenetic vulnerabilities.
基金National Natural Science Foundation of China(Grant Nos.32070838 and 82301874)Open Fund of State Key Laboratory of Reproductive Medicine,Nanjing Medical University(Grant No.SKLRM K202102)。
文摘Meiotic resumption in mammalian oocytes involves nuclear and organelle structural changes,notably the chromatin configuration transition from a non-surrounding nucleolus(NSN)to surrounding nucleolus(SN)in germinal vesicle oocytes.In the current study,we found that nuclear speckles(NSs),a subnuclear structure mainly composed of serine-arginine(SR)proteins,changed from a diffuse spotted distribution in mouse NSN oocytes to an aggregated pattern in SN oocytes.We also found that the SR protein-specific kinase 1(SRPK1),an enzyme that phosphorylates SR proteins,co-localized with NSs at the SN stage,and that NSN oocytes failed to transition to SN oocytes after the inhibition of SRPK1 activity.Furthermore,the typical structure of the chromatin ring around the nucleolus in SN oocytes collapsed after treatment with an SRPK1 inhibitor.Mechanistically,phosphorylated SR proteins were found to be related to chromatin as shown by a salt extraction experiment,and in situ DNaseⅠassay showed that the accessibility of chromatin was enhanced in SN oocytes when SRPK1 was inhibited,accompanied by a decreased repressive modification on histone and the abnormal recurrence of a transcriptional signal.In conclusion,our results indicated that SRPK1-regulated phosphorylation of SR proteins was involved in the NSN-SN transition and played an important role in maintaining the condensed nucleus of SN oocytes via interacting with chromatin.
基金supported by the National Natural Science Foundation of China(32130109 and 32373113)the National Natural Science Foundation of Shanghai(23ZR1426800)SciTech Funding by CSPFTZ Lingang Special Area Marine Biomedical Innovation Platform.
文摘Temperature fluctuations challenge ectothermic species,particularly tropical fish dependent on external temperatures for physiological regulation.However,the molecular mechanisms through which low-temperature stress impacts immune responses in these species,especially in relation to chromatin accessibility and epigenetic regulation,remain poorly understood.In this study,we investigate chromatin and transcriptional changes in the head kidney and thymus tissues of Nile tilapia(Oreochromis niloticus),a tropical fish of significant economic importance,under cold stress.By analyzing cis-regulatory elements in open chromatin regions and their associated transcription factors(TFs),we construct a comprehensive transcriptional regulatory network(TRN)governing immune responses,including DNA damage-induced apoptosis.Our analysis identifies 119 TFs within the TRN,with Stat1 emerging as a central hub exhibiting distinct binding dynamics under cold stress,as revealed by footprint analysis.Overexpression of Stat1 in immune cells leads to apoptosis and increases the expression of apoptosis-related genes,many of which contain Stat1-binding sites in their regulatory regions,emphasizing its critical role in immune cell survival during cold stress.These results provide insights into the transcriptional and epigenetic regulation of immune responses to cold stress in tilapia and highlight Stat1 as a promising target for enhancing cold tolerance in tropical fish species.
基金supported by the National Natural Science Foundation of China(32172389)the Excellent Youth Foundation of Henan Province,China(232300421029)the Key Research and Development Project of Henan Province,China(221111112200)。
文摘The insect fat body is comparable to the liver and adipose tissue in vertebrates,and plays a pivotal role in energy metabolism,nutrient storage,and reproduction.During metamorphosis,the fat body is disassembled via programmed cell death and cell dissociation.After adult eclosion,the fat body is reconstructed either by repopulation from the remaining juvenile fat body cells or by differentiation from adult progenitor cells.This reconstruction is a prerequisite for initiating the extensive synthesis of vitellogenin(Vg),which is necessary for the maturation of eggs.Despite its significance,the underlying mechanisms of this reconstruction remain inadequately understood.Transcriptome analysis of the fat bodies from migratory locusts at 0-5 days post adult emergence revealed 79 genes associated with chromatin remodeling.Weighted gene co-expression network analysis indicated a positive correlation between chromatin remodeling and fat body reconstitution.Protein-protein interaction analysis revealed that brahma,which encodes the catalytic subunit of the SWI/SNF chromatin remodeling complex,is crucial for post-adult-eclosion fat body development.qRT-PCR analysis demonstrated that the levels of brahma mRNA in the fat body are progressively increased during the previtellogenic stage,then reach the peak and remain elevated in the vitellogenic phase.Furthermore,brahma is expressed in response to gonadotropic juvenile hormone(JH).Knockdown of brahma led to a marked reduction in Vg expression within the fat body,along with arrested ovarian growth.These findings shed light on the involvement of brahmamediated chromatin remodeling in JH-stimulated fat body reconstruction and reproduction of adult female locusts.
文摘Objective:To evaluate how DNA fragmentation index(DFI)and chromatin denaturation index(CDI)relate to semen parameters across different types of male infertility,thereby improving the understanding and assessment of sperm quality.Methods:A prospective and descriptive cohort study was conducted over two years at the Integrated Physiology Laboratory of the University of Carthage in collaboration with the Alyssa Fertility Group,Tunisia.A total of 163 participants were classified into five groups based on their semen parameters:normozoospermia,oligozoospermia,asthenozoospermia,teratozoospermia,and oligoastheno-teratozoospermia.The normozoospermia group was selected from volunteers who had children.Semen samples were analyzed according to WHO guidelines.DFI was measured using Halosperm®and CDI was tested using aniline blue staining.Results:Both DFI and CDI were significantly higher in all infertility groups,with the oligozoospermia group showing the highest DFI and CDI.Negative correlations were found between DFI/CDI and sperm motility,concentration,and morphology in the affected groups.The normozoospermia group served as a control with the lowest DFI and CDI values.Conclusions:DFI and CDI are increasingly recognized as important biomarkers for evaluating sperm quality in cases of male infertility.Their elevated levels in patients with oligozoospermia,asthenozoospermia,teratozoospermia,and oligo-asthenoteratozoospermia underscore their potential role in not only diagnosing male infertility but also in assessing the overall reproductive outcomes for affected individuals,thus guiding more effective treatment strategies.
基金supported by the National Natural Science Foundation of China(32070656)。
文摘Rice(Oryza sativa)is a staple food for more than half of the world's population and a critical crop for global agriculture.Understanding the regulatory mechanisms that control gene expression in the rice genome is fundamental for advancing agricultural productivity and food security.In mechanism,cis-regulatory elements(including promoters,enhancers,silencers,and insulators)are key DNA sequences whose activities determine the spatial and temporal expression patterns of nearby genes(Yocca and Edger,2022;Schmitz et al.,2022).
文摘Total or severe teratospermia affects the prognosis of fertility and causes serious problems for patients undergoing assisted reproduction[1].The pathophysiological mechanism of teratospermia is unclear.It has been shown that patients with sperm parameters abnormalities and abnormal morphology have a high rate of fragmentation and sperm DNA decondensation[2,3],and that sperm DNA fragmentation analysis could be used as a predictor factor of fertility potential[4].
基金supported by grants fromthe Shenzhen Medical Research Fund(Grant No.A2302040).
文摘During cellular proliferation DNA undergoes frequent rep-lication cycles in which errors inevitably accumulate.DNA simultaneously faces continuous damage from endogenous sources[e.g.,reactive oxygen species(ROS)]and environmen-tal stressors,such as ultraviolet(UV)and ionizing radiation(IR).Such lesions compromise genomic stability and may escalate into DNA double-strand breaks(DSBs).Failure to repair DSBs can ultimately trigger cell death1.
基金the open research project of State Key Laboratory of Oral Diseases(no.SKLOD2024OF03)the Key Project of Natural Science Research in Anhui Provincial Universities(no.2024AH050683)+1 种基金Anhui Province Outstanding Young Teachers Development Program(no.YQYB2024013)the National Natural Science Foundation of China(no.82201026,82125006).
文摘Ribosomal RNA(rRNA)synthesis is intricately tied to cellular growth and proliferation.Basic fibroblast growth factor(FGF2),a pivotal factor for bone marrow mesenchymal stem cells(BMSCs),can stimulates rRNA transcription,though the underlying mechanism remains unknown.Here,we demonstrate that the cytoplasm-nucleus translocation of FGF2 is determined by the stable nuclear localization motif.Meanwhile,the nuclear FGF2 regulates rRNA expression and BMSCs proliferation via phase separation.Next,through FGF2 related epigenomics and 3D genomes analysis,we identified chromatin architectures during BMSCs differentiation and aging.In the process,topologically associating domains(TADs)and chromatin loops profiling revealed the attenuated genomic interaction among proximal chromosomes 13,14,15,21,and 22,where phase-separated FGF2 facilitates rDNA transcription depend on specific super-enhancers(SEs).Furthermore,we validated that FGF2 orchestrates rDNA chromatin architecture in coordination with STAT5.Together,these findings underscore the pivotal role of FGF2 in rDNA chromatin architectures,which determines BMSCs cell fate.
文摘Wiedemann-Steiner syndrome(OMIM#605130)is a rare congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature;consistent facial features,including long eyelashes,thick or arched eyebrows with a lateral flare,wide nasal bridge,and downslanting and vertically narrow palpebral fissures;mild to moderate intellectual disability;behavioral difficulties;and hypertrichosis on the back.It is caused by heterozygous pathogenic variants in KMT2A.This gene has an established role in histone methylation,which explains the overlap of Wiedemann-Steiner syndrome with other chromatinopathies,a heterogeneous group of syndromic conditions that share a common trigger:The disruption of one of the genes involved in chromatin modification,leading to dysfunction of the epigenetic machinery.
基金This work was supported by the grant from the National Natural Science Foundation of China(No.30393110).
文摘The eukaryotic genome is organized into functionally and structurally distinct domains, representing regulatory unitsfor gene expression and chromosome behavior. DNA sequences that mark the border between adjacent domains are theinsulators or boundary elements, which are required in maintenance of the function of different domains. Some insula-tors need others enable to play insulation activity. Chromatin domains are defined by distinct sets of post-translationallymodified histones. Recent studies show that these histone modifications are also involved in establishment of sharpchromatin boundaries in order to prevent the spreading of distinct domains. Additionally, in some loci, the high-orderchromatin structures for long-range looping interactions also have boundary activities, suggesting a correlation betweeninsulators and chromatin loop domains. In this review, we will discuss recent progress in the field of chromatin domainboundaries.
文摘Diagnosis of male infertility has mainly been based on the World Health Organization （WHO） manual-based semen parameter＇s concentration, motility and morphology. It has, however, become apparent that none of these parameters are reliable markers for evaluation of the fertility potential of a couple. A search for better markers has led to an increased focus on sperm chromatin integrity testing in fertility work-up and assisted reproductive techniques. During the last couple of decades, numerous sperm DNA integrity tests have been developed. These are claimed to be characterized by a lower intraindividual variation, less intralaboratory and interlaboratory variation and thus less subjective than the conventional sperm analysis. However, not all the sperm chromatin integrity tests have yet been shown to be of clinical value. So far, the test that has been found to have the most stable clinical threshold values in relation to fertility is the sperm chromatin structure assay （SCSA）, a flow cytometric test that measures the susceptibility of sperm DNA to acid-induced DNA denaturation in situ. Sperm DNA fragmentation as measured by SCSA has shown to be an independent predictor of successful pregnancy in first pregnancy planners as well as in couples undergoing intrauterine insemination, and can be used as a tool in investigation, counseling and treatment of involuntary childlessness. More conflicting data exist regarding the role of sperm DNA fragmentation in relation to fertilization, pre-embryo development and pregnancy outcome in in vitro fertilization and intracytoplasmic sperm injection （ICSI）.
文摘Spermiogenesis is a complex process leading to the formation of motile spermatozoa characterized by a highly stable chromatin compaction that transfers the paternal genome into the oocyte. It is commonly held that these haploid cells are devoid of transcriptional and translational activities and that the transcripts represent remnants of stored mRNAs. Recently, the chromatin organization of mature spermatozoa has been revisited as a double nucleoprotamine-nucleohistone structure possessing less-condensed regions sensitive to nuclease activity, which could be implicated in the expression of genes involved in the early embryo development. The existence of a complex population of mRNAs in human sperm is well-documented, but their role is not yet elucidated. Evidence for a latent transcriptional capacity and/or a potential de novo translation in mature spermatozoa from fertile men are essential for understanding the last steps of sperm maturation, such as capacitation and acrosome reaction. As such, we have documented the relationship between sperm quality and the distribution of sperm RNAs by showing divergent levels of transcripts encoding for proteins involved in either nuclear condensation （protamines 1 and 2） or in capacitation （eNOS and nNOS, c-myc） or in motility and sperm survival （aromatase） between low and high motile sperm issued from the same sample. Therefore, analyzing the profile of mRNAs could be helpful either as a diagnostic tool for evaluating male fertility after spermatogenesis or for prognosis use for fertilization.
基金ACKNOWLEDGMENTS This study was supported by grants from the Natural Science Foundation of Shanghai （No. 10JC1410800）. The support of Jian-Bin Liu in collecting the patient data is gratefully acknowledged.
文摘The aim of this study was to investigate whether the sperm chromatin structure assay （SCSA） results after swim-up are related to fertilization rates, embryo quality and pregnancy rates following in vitrofertilization （IVF）. A total of 223 couples undergoing IVF in our hospital from October 2008 to September 2009 were included in this study. Data on the IVF process and sperm chromatin structure assay results were collected. Fertilization rate, embryo quality and IVF success rates of different DNA fragmentation index （DFI） subgroups and high DNA stainability （HDS） subgroups were compared. There were no significant differences in fertilization rate, clinical pregnancy or delivery rates between the DFI and HDS subgroups. However, the group with abnormal DFI had a lower good embryo rate. So, we concluded that the SCSA variables, either DFI or HDS after swim-up preparation, were not valuable in predicting fertilization failure or pregnancy rate, but an abnormal DFI meant a lower good embryo rate following IVF.
基金Supported by Grants P302/12/G157 and 13-07822S from the Grant Agency of the Czech Republicby COST-CZ project LD11020 of the Ministry of Education Youth and Sport of the Czech RepublicBártová E is a coordinator of the EU Marie Curie Project PIRSES-GA-2010-269156-LCS
文摘The study of embryonic stem cells is in the spotlight in many laboratories that study the structure and function of chromatin and epigenetic processes. The key properties of embryonic stem cells are their capacity for selfrenewal and their pluripotency. Pluripotent stem cells are able to differentiate into the cells of all three germ layers, and because of this property they represent a promising therapeutic tool in the treatment of diseases such as Parkinson's disease and diabetes, or in the healing of lesions after heart attack. As the basic nuclear unit, chromatin is responsible for the regulation of the functional status of cells, including pluripotency and differentiation. Therefore, in this review we discuss the functional changes in chromatin during differentiation and the correlation between epigenetics events and the differentiation potential of embryonic stem cells. In particular we focus on post-translational histone modification, DNA methylation and the heterochromatin protein HP1 and its unique function in mouse and human embryonic stem cells.
文摘The classical idea about the function of the mammalian sperm chromatin is that it serves to transmit a highly protected and transcriptionally inactive paternal genome, largely condensed by protamines, to the next generation. In addition, recent sperm chromatin genome-wide dissection studies indicate the presence of a differential distribution of the genes and repetitive sequences in the protamine-condensed and histone-condensed sperm chromatin domains, which could be potentially involved in regulatory roles after fertilization. Interestingly, recent proteomic studies have shown that sperm chromatin contains many additional proteins, in addition to the abundant histones and protamines, with specific modifications and chromatin affinity features which are also delivered to the oocyte. Both gene and protein signatures seem to be altered in infertile patients and, as such, are consistent with the potential involvement of the sperm chromatin landscape in early embryo development. This present work reviews the available information on the composition of the human sperm chromatin and its epigenetic potential, with a particular focus on recent results derived from high-throughput genomic and proteomic studies. As a complement, we provide experimental evidence for the detection of phosphorylations and acetylations in human protamine 1 using a mass spectrometry approach. The available data indicate that the sperm chromatin is much more complex than what it was previously thought, raising the possibility that it could also serve to transmit crucial paternal epigenetic information to the embryo.
基金supported by the Agricultural Science and Technology Innovation Program(ASTIP-IAS02).
文摘Background:The development of skeletal muscle in pigs during the embryonic stage is precisely regulated by transcriptional mechanisms,which depend on chromatin accessibility.However,how chromatin accessibility plays a regulatory role during embryonic skeletal muscle development in pigs has not been reported.To gain insight into the landscape of chromatin accessibility and the associated genome-wide transcriptome during embryonic muscle development,we performed ATAC-seq and RNA-seq analyses of skeletal muscle from pig embryos at 45,70 and 100 days post coitus(dpc).Results:In total,21,638,35,447 and 60,181 unique regions(or peaks)were found across the embryos at 45 dpc(LW45),70 dpc(LW70)and 100 dpc(LW100),respectively.More than 91%of the peaks were annotated within−1 kb to 100 bp of transcription start sites(TSSs).First,widespread increases in specific accessible chromatin regions(ACRs)from embryos at 45 to 100 dpc suggested that the regulatory mechanisms became increasingly complicated during embryonic development.Second,the findings from integrated ATAC-seq and RNA-seq analyses showed that not only the numbers but also the intensities of ACRs could control the expression of associated genes.Moreover,the motif screening of stage-specific ACRs revealed some transcription factors that regulate muscle developmentrelated genes,such as MyoG,Mef2c,and Mef2d.Several potential transcriptional repressors,including E2F6,OTX2 and CTCF,were identified among the genes that exhibited different regulation trends between the ATAC-seq and RNA-seq data.Conclusions:This work indicates that chromatin accessibility plays an important regulatory role in the embryonic muscle development of pigs and regulates the temporal and spatial expression patterns of key genes in muscle development by influencing the binding of transcription factors.Our results contribute to a better understanding of the regulatory dynamics of genes involved in pig embryonic skeletal muscle development.
基金the National Natural Science Foundation of China(31922061,41871044,31500502,31561123001,and 31590821)US National Science Foundation grants(DEB-1542599)+3 种基金the National Key Research and Development Program of China(2016YFD0600101 and 2017YFC0505203)the National Science and Technology Major Project(2018ZX10201002)the National Key Project for Basic Research(2012CB114504)Fundamental Research Funds for the Central Universities(2020SCUNL103,2018CDDY-S02-SCU,and SCU2019D013).
文摘The nonrandom three-dimensional organization of chromatin plays an important role in the regulation of gene expression.However,it remains unclear whether this organization is conserved and whether it is involved in regulating gene expression during speciation after whole-genome duplication(WGD)in plants.In this study,high-resolution interaction maps were generated using high-throughput chromatin conformation capture(Hi-C)techniques for two poplar species,Populus euphratica and Populus alba var.pyramidalis,which diverged~14 Mya after a common WGD.We examined the similarities and differences in the hierarchical chromatin organization between the two species,including A/B compartment regions and topologically associating domains(TADs),as well as in their DNA methylation and gene expression patterns.We found that chromatin status was strongly associated with epigenetic modifications and gene transcriptional activity,yet the conservation of hierarchical chromatin organization across the two species was low.The divergence of gene expression between WGD-derived paralogs was associated with the strength of chromatin interactions,and colocalized paralogs exhibited strong similarities in epigenetic modifications and expression levels.Thus,the spatial localization of duplicated genes is highly correlated with biased expression during the diploidization process.This study provides new insights into the evolution of chromatin organization and transcriptional regulation during the speciation process of poplars after WGD.
基金supported by the National Natural Science Foundation of China(31830045,32025005)。
文摘Plant reproduction requires the coordinated development of both male and female reproductive organs.Jasmonic acid(JA)plays an essential role in stamen filament elongation.However,the mechanism by which the JA biosynthesis genes are regulated to promote stamen elongation remains unclear.Here,we show that the chromatin remodeling complex Imitation of Switch(ISWI)promotes stamen filament elongation by regulating JA biosynthesis.We show that AT-Rich Interacting Domain 5(ARID5)interacts with CHR11,CHR17,and RLT1,several known subunits of ISWI.Mutations in ARID5 and RLTs caused a reduced seed set due to greatly shortened stamen filaments.RNA-seq analyses reveal that the expression of key genes responsible for JA biosynthesis is significantly down-regulated in the arid5 and rlt mutants.Consistently,the JA levels are drastically decreased in both arid5 and rlt mutants.Chromatin immunoprecipitationquantitative PCR analyses further show that ARID5 is recruited to the chromatin of JA biosynthesis genes.Importantly,exogenous JA treatments can fully rescue the defects of stamen filament elongation in both arid5 and rlt mutants,leading to the partial recovery of fertility.Our results provide a clue how JA biosynthesisis positively regulated by the chromatin remodeling complex ISWI,thereby promoting stamen filament elongation in Arabidopsis.
