Summary It was noted that circadian components function in plant adaptation to diurnal temperature cycles and freezing tolerance. Our genome-wide transcriptome analysis revealed that evening-phased COR27 and COR28 mai...Summary It was noted that circadian components function in plant adaptation to diurnal temperature cycles and freezing tolerance. Our genome-wide transcriptome analysis revealed that evening-phased COR27 and COR28 mainly repress the transcription of clockassociated evening genes PRRS, ELF4 and cold-responsive genes. Chromatin immunoprecipitation indicated that CCAI is recruited to the site containing EE elements of COR27 and COR28 promoters in a temperaturedependent way. Further genetic analysis shows COR28 is essential for the circadian function of PRR9 and PRRT. Together, our results support a role of COR27 and COR28 as nighttime repressors integrating circadian clock and plant cold stress responses.展开更多
PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different patho...PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.展开更多
Anthocyanins are important metabolites that provide a red or blue-purple hue to plants.The biosynthesis of these metabolites is mainly activated by the MYB-bHLH-WD40(MBW)complex and repressed by a wide variety of prot...Anthocyanins are important metabolites that provide a red or blue-purple hue to plants.The biosynthesis of these metabolites is mainly activated by the MYB-bHLH-WD40(MBW)complex and repressed by a wide variety of proteins.Studies have shown that MYB activators activate MYB repressors to balance anthocyanin biosynthesis.However,there is a scarcity of studies investigating this mechanism in grapes.To explore the transcription factors involved in the regulation of anthocyanin biosynthesis,we reanalyzed the RNA-seq database for different developmental stages of‘Muscat Hamburg'berries,and the R2R3-MYB gene,annotated as VvMYB3,was screened.Our study revealed the anthocyanin content of the grape cultivar‘Y73'was higher than that of its parental cultivar MH,and the putative repressor VvMYB3 was found to be highly expressed in‘Y73'by qRT-PCR.The calli transgenic assays demonstrated that the repressive activity of VvMYB3 was conferred by the b HLH-binding motif,as well as by the C1 and C2 motifs.Yeast hybridization and chip-PCR assays revealed that VvMYB3 could repress anthocyanin biosynthesis by competing with VvMYBA1 to bind to VvMYC1 and promoting histone deacetylation of VvUFGT via the C2 motif.However,the expression of VvMYB3 was activated by VvMYBA1,which forms a negative feedback regulatory loop to modulate anthocyanin accumulation.In addition,we found a 408-bp repeat tandem sequence insertion in the VvMYBA1 promoter region of‘Y73'by sequencing.The GUS activity analysis showed that this sequence enhanced the expression of VvMYBA1 and led to an excessive accumulation of anthocyanins.Overall,our results provide insights into the anthocyanin activator-repressor system in grapes that prevents overaccumulation of anthocyanins.展开更多
Enhancer of zeste homolog 2(EZH2)is a key epigenetic regulatory protein and enzyme catalytic subunit of the polycomb repressor complex 2(PRC2),responsible for catalyzing the trimethylation of histone H3K27 and subsequ...Enhancer of zeste homolog 2(EZH2)is a key epigenetic regulatory protein and enzyme catalytic subunit of the polycomb repressor complex 2(PRC2),responsible for catalyzing the trimethylation of histone H3K27 and subsequent repression of gene transcription.Abnormal EZH2 expression or mutation is associated with various cancers,particularly lymphoma,and breast and prostate cancer.EZH2 has been investigated as an important target in cancer therapy and potential EZH2-targeted drugs have been developed.This article reviews the research progress on the mechanism of transcriptional regulation of EZH2 and the development and clinical use of some inhibitors targeting EZH2.展开更多
Petal blotch is a prevalent pigmentation pattern observed in the Xibei tree peony(Paeonia rockii), possessing significant aesthetic value and playing a crucial role in the species' reproduction and fitness. Despit...Petal blotch is a prevalent pigmentation pattern observed in the Xibei tree peony(Paeonia rockii), possessing significant aesthetic value and playing a crucial role in the species' reproduction and fitness. Despite years of research, deciphering the molecular mechanisms underlying blotch formation remains challenging. As is well known, floral pigmentation is frequently associated with the familiar R2R3-MYB transcription factors. The key MYB anthocyanin activators of P. rockii ‘Shu Sheng Peng Mo' were previously reported in our preceding study. In this study, we identified and characterized three R2R3-MYBs, Pr MYBi1, Pr MYBi2, and Pr MYBi3, which belong to subgroup 4(SG4) and play repressor roles in anthocyanin biosynthesis. A quantitative real-time PCR(q RT-PCR) assay indicated that the expression of Pr MYBi1 and Pr MYBi3 gradually increased during flowering development and was substantially up-regulated in non-blotch compared to blotch. Yeast one-hybrid and dualluciferase assays demonstrated that Pr MYBi(1-3) directly target the anthocyanin structural genes and repress their transcription. The genetic transformation of tobacco demonstrated that the overexpression of Pr MYBi(1-3) decreased anthocyanin accumulation in flowers, with Pr MYBi1 serving as the most effective repressor. Our results revealed that SG4 R2R3-MYBs negatively regulate the anthocyanin pathway in P.rockii conservatively, and we provide the definite members. These findings will advance future research to unravel the mystery of blotch pattern formation.展开更多
BACKGROUND Esophageal cancer(ESCA)poses a significant challenge in oncology because of the limited treatment options and poor prognosis.Therefore,enhancing the therapeutic effects of radiotherapy for ESCA and identify...BACKGROUND Esophageal cancer(ESCA)poses a significant challenge in oncology because of the limited treatment options and poor prognosis.Therefore,enhancing the therapeutic effects of radiotherapy for ESCA and identifying relevant therapeutic targets are crucial for improving both the survival rate and quality of life of patients.AIM To define the role of the transcription factor Snail family transcriptional repressor 1(SNAI1)in ESCA,particularly its regulation of radiosensitivity.METHODS A comprehensive analysis of TCGA data assessed SNAI1 expression in ESCA.Survival curves correlated SNAI1 levels with radiotherapy outcomes.Colony formation assays,flow cytometry,and a xenograft model were used to evaluate tumor radiosensitivity and apoptosis.Western blot validated protein expression,while Chromatin im-munoprecipitation assays examined SNAI1's role in regulating epithelial-mesenchymal transition(EMT).RESULTS SNAI1 expression in ESCA cell lines and clinical specimens emphasizes its central role in this disease.Elevated SNAI1 expression is correlated with unfavorable outcomes in radiotherapy.Downregulation of SNAI1 enhances the sensitivity of ESCA cells to ionizing radiation(IR),resulting in remarkable tumor regression upon IR treatment in vivo.This study underscores the direct involvement of SNAI1 in the regulation of EMT,particularly under IR-induced conditions.Furthermore,inhibiting deacetylation effectively suppresses EMT,suggesting a potential avenue to enhance the response to radiotherapy in ESCA.CONCLUSION This study highlights SNAI1's role in ESCA radiosensitivity,offering prognostic insights and therapeutic strategies to enhance radiotherapy by targeting SNAI1 and modulating EMT processes.展开更多
miRNAs are a class of small, ∽22nt, non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. They play profound and pervasive roles in manipulating gene expression involved in cell d...miRNAs are a class of small, ∽22nt, non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. They play profound and pervasive roles in manipulating gene expression involved in cell development, proliferation and apoptosis in various eukaryotes, which, in theory, could provide an access to many human diseases in theory. Recent evidence demonstrates that aberrant miRNA expression is a hallmark of tumor development, revealing that miRNA genes could function as potential oncogenes and repressors in the human body. miRNAs can affect tumorigenesis mainly by interrupting the cell cycle at the cellular level and by interacting with signaling, oncogenes and with the response to environmental factors at the molecular level. The established miRNA expression signature could be a potent tool to diagnose and treat human cancers in the future.展开更多
In response to dynamically altered environments,plants must finely coordinate the balance between growth and stress responses for their survival.However,the underpinning regulatory mechanisms remain largely elusive.Th...In response to dynamically altered environments,plants must finely coordinate the balance between growth and stress responses for their survival.However,the underpinning regulatory mechanisms remain largely elusive.The phytohormone gibberellin promotes growth via a derepression mechanism by proteasomal degradation of the DELLA transcription repressors.Conversely,the stress-induced burst of nitric oxide(NO)enhances stress tolerance,largely relying on NO-mediated S-nitrosylation,a redox-based posttranslational modification.Here,we show that S-nitrosylation of Cys-374 in the Arabidopsis RGA protein,a key member of DELLAs,inhibits its interaction with the F-box protein SLY1,thereby preventing its proteasomal degradation under salinity condition.The accumulation of RGA consequently retards growth but enhances salt tolerance.We propose that NO negatively regulates gibberellin signaling via S-nitrosylation of RGA to coordinate the balance of growth and stress responses when challenged by adverse environments.展开更多
AIM: Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions...AIM: Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS: Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS: There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION: The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.展开更多
Androgen receptor (AR), a hormonal transcription factor, plays important roles during prostate cancer progression and is a key target for therapeutic interventions. While androgen-deprivation therapies are initially s...Androgen receptor (AR), a hormonal transcription factor, plays important roles during prostate cancer progression and is a key target for therapeutic interventions. While androgen-deprivation therapies are initially successful in regressing prostate tumors, the disease ultimately comes back as castration-resistant prostate cancer (CRPC) or at the late stage as neuroendocrine prostate cancer (NEPC). CRPC remains largely dependent on hyperactive AR signaling in the milieu of low androgen, while NEPC is negative of AR expression but positive of many AR-repressed genes. Recent technological advances in genome-wide analysis of transcription factor binding sites have revealed an unprecedented set of AR target genes. In addition to its well-known function in activating gene expression, AR is increasingly known to also act as a transcriptional repressor. Here, we review the molecular mechanisms by which AR represses gene expression. We also summarize AR-repressed genes that are aberrantly upregulated in CRPC and NEPC and represent promising targets for therapeutic intervention.展开更多
Germlines in plants are formed de novo during post-embryonic development, while little is known about the mechanism that controls this process. In Arabidopsis, the earliest gene controlling this process is SPOROCYTELE...Germlines in plants are formed de novo during post-embryonic development, while little is known about the mechanism that controls this process. In Arabidopsis, the earliest gene controlling this process is SPOROCYTELESS （SPL）. A decade ago, we showed that loss of SPL function abolished sporogenesis in both male and female organs of Arabidopsis. However, its function is unclear up to now. In this study, we showed that SPL belongs to a novel transcription repressor family specific in embryophyte, which consists of 173 members in the land plants so far. All of them contain a conserved SPL-motif in their N-terminal and an ethylene-responsive element binding factor-associated amphiphilic repression （EAR） motif in the C-terminal, therefore designated as SPL-like, EAR-containing proteins （SPEARs）. Consis- tently, SPL acts as a transcriptional repressor in yeast and tobacco cells, and SPEAR proteins are able to form homodimer and/or het- erodimer with each other in vitro. Furthermore, SPEARs interact with the TOPLESS （TPL） co-repressors via the EAR motif and TCP family transcription factors in yeast cells. Together, we propose that SPL and SPEARs most likely belong to a novel transcription repressor family in land plants which may play a variety of developmental roles in plants.展开更多
AIM:To explore the expression and function of slug,a transcriptional repressor,in human intrahepatic cholangiocarcinoma(IHCC)and identify its role in IHCC progression.METHODS:Expression of slug was detected in 36 case...AIM:To explore the expression and function of slug,a transcriptional repressor,in human intrahepatic cholangiocarcinoma(IHCC)and identify its role in IHCC progression.METHODS:Expression of slug was detected in 36 cases of IHCC and 12 cases of normal intrahepatic bile ducts and liver parenchyma by immunohistochemistry.The patients were divided into low slug expression group(< 20%of carcinoma cells stained)and high slug expression group(≥20%of carcinoma cells stained).Slug expression was correlated with clinicopathological parameters of IHCC patients.The patients were defined as short-term survivors if their survival time was<12 mo and as longterm survivors if their survival time was≥12 mo.RESULTS:Slug was not expressed in normal liver epi-thelium samples,lowly expressed in 15 tissue samples (10-,5+)and highly expressed in 21 tissue samples (16++;5+++)from IHCC patients.The survival rate of patients with a low slug expression was 33.3%(n =5)and 66.7%(n=10),respectively.The survival rate of patients with a high slug expression was 61.9% (n=13)and 38.1%(n=8),respectively(P=0.02).Lymph node metastasis was found in 4(26.7%)out of the 15 patients with a low slug expression and in 14(66.7%)out of the 21 patients with a high slug expression,respectively.The incidence rate of lymph node metastasis increased with the increasing slug expression level(P=0.003),and higher in patients with a high slug expression than in those with a low slug expression.Slug expression did not significantly correlate with the tumor size and stage or histologic grade,or with the gender and age of patients.CONCLUSION:Slug expression is a novel prognostic marker for IHCC with lymph node metastasis.展开更多
CONSTANS,CO-like,and TOC1(CCT)family genes play important roles in regulating heading date,which exerts a large impact on the regional and seasonal adaptation of rice.Previous studies have shown that Grain number,plan...CONSTANS,CO-like,and TOC1(CCT)family genes play important roles in regulating heading date,which exerts a large impact on the regional and seasonal adaptation of rice.Previous studies have shown that Grain number,plant height,and heading date2(Ghd2)exhibits a negative response to drought stress by directly upregulating Rubisco activase and exerting a negative effect on heading date.However,the target gene of Ghd2 regulating heading date is still unknown.In this study,CO3 is identified by analyzing Ghd2 ChIP-seq data.Ghd2 activates CO3 expression by binding to the CO3 promoter through its CCT domain.EMSA experiments show that the motif CCACTA in the CO3 promoter was recognized by Ghd2.A comparison of the heading dates among plants with CO3 knocked out or overexpressed and double-mutants with Ghd2 overexpressed and CO3 knocked out shows that CO3 negatively and constantly regulates flowering by repressing the transcription of Ehd1,Hd3a,and RFT1.In addition,the target genes of CO3 are explored via a comprehensive analysis of DAP-seq and RNA-seq data.Taken together,these results suggest that Ghd2 directly binds to the downstream gene CO3,and the Ghd2eCO3 module constantly delays heading date via the Ehd1-mediated pathway.展开更多
Alternative splicing （AS） is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence impli...Alternative splicing （AS） is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence implicates splice isoforms in most if not all hallmarks of cancer, including growth, apoptosis, invasion and metastasis, angiogenesis, and metabolism. AS has important clinical implications since it can be manipulated therapeutically to treat cancer and represents a mechanism of resistance to therapy. In prostate cancer （PCa） AS also plays a prominent role and this review will summarize the current knowledge of alternatively spliced genes with important functional consequences. We will highlight accumulating evidence on AS of the components of the two critical pathways in PCa： androgen receptor （AR） and phosphoinositide 3-kinase （PI3K）. These observations together with data on dysregulation of splice factors in PCa suggest that AR and PI3K pathways may be interconnected with previously unappreciated splicing regulatory networks. In addition, we will discuss several lines of evidence implicating splicing regulation in the development of the castration resistance.展开更多
Objective： Id2 is a natural inhibitor of the basic helix-loop-helix（bHLH） transcription factors. Although it is well known that active ld2 prevents differentiation and promotes cell cycle progression and tumorigene...Objective： Id2 is a natural inhibitor of the basic helix-loop-helix（bHLH） transcription factors. Although it is well known that active ld2 prevents differentiation and promotes cell cycle progression and tumorigenesis, the molecular events that regulate Id2 activity remain to be investigated. Methods： Yeast two-hybrid, mammalian two-hybrid, GST-pulldown and immunoprecipitation （ColP） assays were used to screen and identify novel Id2 interactors. Luciferase assays were used to detect E47-mediated transcription activity. Colony formation and BrdU incorporation assays were used to determine cellular proliferation abilities. Northorn blot, western blot and quantitative PCR methods were used to measure gene expression levels. Electrophoretic mobility shift assays （EMSAs） were performed to investigate protein/DNA binding. Results： The LIM-only protein FHL2 （four-and-a-half-LIM-only protein 2） was identified to be a novel Id2 interactor. The HLH domain within Id2 is not required for its interaction with FHL2. FHL2 antagonizes the inhibitory effect of Id2 on the basic helix-loop-helix protein E47-mediated transcription. FHL2 prevents the formation of Id2-E47 heterdimer, thus releasing E47 to its target DNA and restoring its transcriptional activity. FHL2 expression was remarkably up-regulated during retinoic acid-induced differentiation of neuroblastoma cells, during which the expression of Id2 is opposite to that. Ectopic FHL2 expression in neuroblastoma cells markedly reduces the transcriptional and cell-cycle promoting functions of Id2. Conclusion： These results indicate that FHL2 is an important repressor of the oncogenic activity of Id2 in neuroblastoma cells.展开更多
AIM: To investigate a novel therapeutic strategy to target and suppress c-myc in human cancers using far up stream element (FUSE)-binding protein-interacting repressor (FIR).
Objective：FHL2 was previously identified to be a novel interacting factor of Id family proteins.The aim of this study was to investigate,the effects of FHL2 on Id1-mediated transcriptional regulation activity and its...Objective：FHL2 was previously identified to be a novel interacting factor of Id family proteins.The aim of this study was to investigate,the effects of FHL2 on Id1-mediated transcriptional regulation activity and its oncogenic activity in human breast cancer cells.Methods：Cell transfection was performed by Superfect reagent.Id1 stably overexpressed MCF-7 cells was cloned by G418 screening.The protein level of Id1 was detected by western blot analysis.Dual relative luciferase assays were used to measure the effect of E47-mediated transcriptional activity in MCF-7 human breast cancer cells.MTT assay was used to measure cell proliferation.Transwell assay was used to measure the invasive capacity of MCF-7 cancer cells.Results：The basic helix-loop-helix（bHLH） factor E47-mediated transcription activity was markedly repressed by Id1 in MCF-7 cells.This Id1-mediated repression was effectively antagonized by FHL2 transduction.Overexpression of Id1 markedly promoted the proliferation rate and invasive capacity of MCF-7 cells;however,these effects induced by Id1 were significantly suppressed by overexpression of FHL2 in cells.Conclusion：FHL2 can inhibit the proliferation and invasiveness of human breast cancer cells by repressing the functional activity of Id1.These findings provide the basis for further investigating the functional roles of FHL2-Id1 signaling in the carcinogenesis and development of human breast cancer.展开更多
Retrotransposons,a type of DNA fragment that can mobilize itself on genome,can generate genetic variations and develop for molecular markers based on the insertion polymorphism.Zinc finger proteins(ZNFs)are among the ...Retrotransposons,a type of DNA fragment that can mobilize itself on genome,can generate genetic variations and develop for molecular markers based on the insertion polymorphism.Zinc finger proteins(ZNFs)are among the most abundant proteins in eukaryotic animals,and their functions are extraordinarily diverse and particularly important in gene regulation.In the current study,bioinformatic prediction was performed to screen for retrotransposon insertion polymorphisms(RIPs)in six ZNF genes(ZNF2,ZNF3,ZNF7,ZNF8,ZNF10 and ZNF12).Six RIPs in these ZNFs,including one short interspersed nuclear element(SINE)RIP in intron 1 and one long interspersed nuclear element 1(L1)RIP in intron 3 of ZNF2,one SINE RIP in 5′flanking region and one SINE RIP in intron 2 of ZNF3,one SINE RIP in 3′UTR of ZNF7 and one L1 RIP in intron 2 of ZNF12,were discovered and their presence was confirmed by PCR.The impact of the SINE RIP in the first intron of ZNF2,which is close to the core promoter of ZNF2,on the gene activity was investigated by dual-luciferase assay in three cell lines.Our results showed that the SINE insertion in the intron 1 of ZNF2 repressed the core promoter activity extremely significantly(P<0.01)in cervical cancer cells and porcine primary embryonic fibroblasts(HeLa and PEF),thus SINE may act as a repressor.This SINE RIP also significantly(P<0.05)affected the corrected back fat thickness in Yorkshire pigs.The corrected back fat thickness of individuals with SINE insertion in the first intron of ZNF2 was significantly(P<0.05)higher than that of individuals without SINE insertion.In summary,our data suggested that RIPs play important roles in the genetic variations of these ZNF genes and SINE RIP in the intron 1 of ZNF2 may provide a useful molecular marker for the screening of fat deposition in the pig breeding.展开更多
L-Arginine is the precursor of nitric oxide(NO),a host immune effector against intracellular pathogens including Mycobacterium tuberculosis(M.tb).Pathogens including M.tb have evolved various strategies targeting argi...L-Arginine is the precursor of nitric oxide(NO),a host immune effector against intracellular pathogens including Mycobacterium tuberculosis(M.tb).Pathogens including M.tb have evolved various strategies targeting arginine to block the production of NO for better survival and proliferation.However,L-arginine metabolism and regulation in Mycobacterium are poorly understood.Here,we report the identification of M.smegmatis MSMEG_1415(homolog of M.tb Rv2324)as an arginine-responsive transcriptional factor regulating the arginase pathway.In the absence of L-arginine,MSMEG_1415 acts as a repressor to inhibit the transcription of the roc(for arginine,ornithine catabolism)gene cluster,thereby switching off the arginase pathway.Treatment with L-arginine relieves the transcriptional inhibition of MSMEG_1415 on the roc gene cluster to activate the arginase pathway.Moreover,the L-arginine-MSMEG_1415 complex activates the transcription of the roc gene cluster by recognizing and binding a 15-bp palindrome motif,thereby preventing the excess accumulation of L-arginine in M.smegmatis.Physiologically,MSMEG_1415 confers mycobacteria resistance to starvation and fluoroquinolones exposure,suggestive of its important role in M.smegmatis persistence.The results uncover a unique regulatory mechanism of arginine metabolism in mycobacteria and identify M.tb Rv2324 as an attractive candidate target for the design of drugs against tuberculosis.展开更多
基金supported by grants from the National Science Foundation of China (31170265)the Program for New Century Excellent Talents in University of the Ministry of Education of China (NCET-13-0771)the Hebei Science Fund for Distinguished Young Scholars (GCC2014063) to X.X
文摘Summary It was noted that circadian components function in plant adaptation to diurnal temperature cycles and freezing tolerance. Our genome-wide transcriptome analysis revealed that evening-phased COR27 and COR28 mainly repress the transcription of clockassociated evening genes PRRS, ELF4 and cold-responsive genes. Chromatin immunoprecipitation indicated that CCAI is recruited to the site containing EE elements of COR27 and COR28 promoters in a temperaturedependent way. Further genetic analysis shows COR28 is essential for the circadian function of PRR9 and PRRT. Together, our results support a role of COR27 and COR28 as nighttime repressors integrating circadian clock and plant cold stress responses.
基金supported by Telethon Italy award GGP15225(to RC and GM)Italian Ministry of Health award RF-2016-02362950(to RC and CZ)+1 种基金the CJD Foundation USA(to RC)the Associazione Italiana Encefalopatie da Prioni(AIEnP)(to RC).
文摘PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.
基金supported by the National Natural Science Foundation of China(Grant No.32202438)the China Agriculture Research System(Grant No.CARS-29)the Agricultural Science and Technology Innovation Program(Grant No.CAASASTIP-ZFRI)。
文摘Anthocyanins are important metabolites that provide a red or blue-purple hue to plants.The biosynthesis of these metabolites is mainly activated by the MYB-bHLH-WD40(MBW)complex and repressed by a wide variety of proteins.Studies have shown that MYB activators activate MYB repressors to balance anthocyanin biosynthesis.However,there is a scarcity of studies investigating this mechanism in grapes.To explore the transcription factors involved in the regulation of anthocyanin biosynthesis,we reanalyzed the RNA-seq database for different developmental stages of‘Muscat Hamburg'berries,and the R2R3-MYB gene,annotated as VvMYB3,was screened.Our study revealed the anthocyanin content of the grape cultivar‘Y73'was higher than that of its parental cultivar MH,and the putative repressor VvMYB3 was found to be highly expressed in‘Y73'by qRT-PCR.The calli transgenic assays demonstrated that the repressive activity of VvMYB3 was conferred by the b HLH-binding motif,as well as by the C1 and C2 motifs.Yeast hybridization and chip-PCR assays revealed that VvMYB3 could repress anthocyanin biosynthesis by competing with VvMYBA1 to bind to VvMYC1 and promoting histone deacetylation of VvUFGT via the C2 motif.However,the expression of VvMYB3 was activated by VvMYBA1,which forms a negative feedback regulatory loop to modulate anthocyanin accumulation.In addition,we found a 408-bp repeat tandem sequence insertion in the VvMYBA1 promoter region of‘Y73'by sequencing.The GUS activity analysis showed that this sequence enhanced the expression of VvMYBA1 and led to an excessive accumulation of anthocyanins.Overall,our results provide insights into the anthocyanin activator-repressor system in grapes that prevents overaccumulation of anthocyanins.
基金supported by the National Natural Science Foundation of China(32360166,31760321).
文摘Enhancer of zeste homolog 2(EZH2)is a key epigenetic regulatory protein and enzyme catalytic subunit of the polycomb repressor complex 2(PRC2),responsible for catalyzing the trimethylation of histone H3K27 and subsequent repression of gene transcription.Abnormal EZH2 expression or mutation is associated with various cancers,particularly lymphoma,and breast and prostate cancer.EZH2 has been investigated as an important target in cancer therapy and potential EZH2-targeted drugs have been developed.This article reviews the research progress on the mechanism of transcriptional regulation of EZH2 and the development and clinical use of some inhibitors targeting EZH2.
基金supported by the National Natural Science Foundation of China(Grant No.32030095)the Key project at central government level:The ability establishment of sustainable use for valuable Chinese medicine resources(Grant No.2060302).
文摘Petal blotch is a prevalent pigmentation pattern observed in the Xibei tree peony(Paeonia rockii), possessing significant aesthetic value and playing a crucial role in the species' reproduction and fitness. Despite years of research, deciphering the molecular mechanisms underlying blotch formation remains challenging. As is well known, floral pigmentation is frequently associated with the familiar R2R3-MYB transcription factors. The key MYB anthocyanin activators of P. rockii ‘Shu Sheng Peng Mo' were previously reported in our preceding study. In this study, we identified and characterized three R2R3-MYBs, Pr MYBi1, Pr MYBi2, and Pr MYBi3, which belong to subgroup 4(SG4) and play repressor roles in anthocyanin biosynthesis. A quantitative real-time PCR(q RT-PCR) assay indicated that the expression of Pr MYBi1 and Pr MYBi3 gradually increased during flowering development and was substantially up-regulated in non-blotch compared to blotch. Yeast one-hybrid and dualluciferase assays demonstrated that Pr MYBi(1-3) directly target the anthocyanin structural genes and repress their transcription. The genetic transformation of tobacco demonstrated that the overexpression of Pr MYBi(1-3) decreased anthocyanin accumulation in flowers, with Pr MYBi1 serving as the most effective repressor. Our results revealed that SG4 R2R3-MYBs negatively regulate the anthocyanin pathway in P.rockii conservatively, and we provide the definite members. These findings will advance future research to unravel the mystery of blotch pattern formation.
基金Supported by the National Key R&D Program of China,No.2022YFC2503700 and No.2022YFC2503703the National Health Commission Key Laboratory of Nuclear Technology Medical Transformation(Mianyang Central Hospital),No.2023HYX005.
文摘BACKGROUND Esophageal cancer(ESCA)poses a significant challenge in oncology because of the limited treatment options and poor prognosis.Therefore,enhancing the therapeutic effects of radiotherapy for ESCA and identifying relevant therapeutic targets are crucial for improving both the survival rate and quality of life of patients.AIM To define the role of the transcription factor Snail family transcriptional repressor 1(SNAI1)in ESCA,particularly its regulation of radiosensitivity.METHODS A comprehensive analysis of TCGA data assessed SNAI1 expression in ESCA.Survival curves correlated SNAI1 levels with radiotherapy outcomes.Colony formation assays,flow cytometry,and a xenograft model were used to evaluate tumor radiosensitivity and apoptosis.Western blot validated protein expression,while Chromatin im-munoprecipitation assays examined SNAI1's role in regulating epithelial-mesenchymal transition(EMT).RESULTS SNAI1 expression in ESCA cell lines and clinical specimens emphasizes its central role in this disease.Elevated SNAI1 expression is correlated with unfavorable outcomes in radiotherapy.Downregulation of SNAI1 enhances the sensitivity of ESCA cells to ionizing radiation(IR),resulting in remarkable tumor regression upon IR treatment in vivo.This study underscores the direct involvement of SNAI1 in the regulation of EMT,particularly under IR-induced conditions.Furthermore,inhibiting deacetylation effectively suppresses EMT,suggesting a potential avenue to enhance the response to radiotherapy in ESCA.CONCLUSION This study highlights SNAI1's role in ESCA radiosensitivity,offering prognostic insights and therapeutic strategies to enhance radiotherapy by targeting SNAI1 and modulating EMT processes.
基金the National Basic Research Program of China (2004CB1175004) and the National Natural Science of Foundation of China, No. 30025034
文摘miRNAs are a class of small, ∽22nt, non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. They play profound and pervasive roles in manipulating gene expression involved in cell development, proliferation and apoptosis in various eukaryotes, which, in theory, could provide an access to many human diseases in theory. Recent evidence demonstrates that aberrant miRNA expression is a hallmark of tumor development, revealing that miRNA genes could function as potential oncogenes and repressors in the human body. miRNAs can affect tumorigenesis mainly by interrupting the cell cycle at the cellular level and by interacting with signaling, oncogenes and with the response to environmental factors at the molecular level. The established miRNA expression signature could be a potent tool to diagnose and treat human cancers in the future.
基金supported by grants from the National Natural Science Foundation of China (31830017 and 31521001)Chinese Academy of Sciences (XDB27030207)State Key Laboratory of Plant Genomics (SKLPG2020-22)
文摘In response to dynamically altered environments,plants must finely coordinate the balance between growth and stress responses for their survival.However,the underpinning regulatory mechanisms remain largely elusive.The phytohormone gibberellin promotes growth via a derepression mechanism by proteasomal degradation of the DELLA transcription repressors.Conversely,the stress-induced burst of nitric oxide(NO)enhances stress tolerance,largely relying on NO-mediated S-nitrosylation,a redox-based posttranslational modification.Here,we show that S-nitrosylation of Cys-374 in the Arabidopsis RGA protein,a key member of DELLAs,inhibits its interaction with the F-box protein SLY1,thereby preventing its proteasomal degradation under salinity condition.The accumulation of RGA consequently retards growth but enhances salt tolerance.We propose that NO negatively regulates gibberellin signaling via S-nitrosylation of RGA to coordinate the balance of growth and stress responses when challenged by adverse environments.
基金the key,project of the tenth-five foundation of PLA,No.01Z011
文摘AIM: Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS: Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS: There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION: The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.
文摘Androgen receptor (AR), a hormonal transcription factor, plays important roles during prostate cancer progression and is a key target for therapeutic interventions. While androgen-deprivation therapies are initially successful in regressing prostate tumors, the disease ultimately comes back as castration-resistant prostate cancer (CRPC) or at the late stage as neuroendocrine prostate cancer (NEPC). CRPC remains largely dependent on hyperactive AR signaling in the milieu of low androgen, while NEPC is negative of AR expression but positive of many AR-repressed genes. Recent technological advances in genome-wide analysis of transcription factor binding sites have revealed an unprecedented set of AR target genes. In addition to its well-known function in activating gene expression, AR is increasingly known to also act as a transcriptional repressor. Here, we review the molecular mechanisms by which AR represses gene expression. We also summarize AR-repressed genes that are aberrantly upregulated in CRPC and NEPC and represent promising targets for therapeutic intervention.
基金financially supported by the National Nature Science Foundation of China(No.30921003)Major Research Plan from the Ministry of Science and Technology of China(No.2013CB945100)
文摘Germlines in plants are formed de novo during post-embryonic development, while little is known about the mechanism that controls this process. In Arabidopsis, the earliest gene controlling this process is SPOROCYTELESS （SPL）. A decade ago, we showed that loss of SPL function abolished sporogenesis in both male and female organs of Arabidopsis. However, its function is unclear up to now. In this study, we showed that SPL belongs to a novel transcription repressor family specific in embryophyte, which consists of 173 members in the land plants so far. All of them contain a conserved SPL-motif in their N-terminal and an ethylene-responsive element binding factor-associated amphiphilic repression （EAR） motif in the C-terminal, therefore designated as SPL-like, EAR-containing proteins （SPEARs）. Consis- tently, SPL acts as a transcriptional repressor in yeast and tobacco cells, and SPEAR proteins are able to form homodimer and/or het- erodimer with each other in vitro. Furthermore, SPEARs interact with the TOPLESS （TPL） co-repressors via the EAR motif and TCP family transcription factors in yeast cells. Together, we propose that SPL and SPEARs most likely belong to a novel transcription repressor family in land plants which may play a variety of developmental roles in plants.
文摘AIM:To explore the expression and function of slug,a transcriptional repressor,in human intrahepatic cholangiocarcinoma(IHCC)and identify its role in IHCC progression.METHODS:Expression of slug was detected in 36 cases of IHCC and 12 cases of normal intrahepatic bile ducts and liver parenchyma by immunohistochemistry.The patients were divided into low slug expression group(< 20%of carcinoma cells stained)and high slug expression group(≥20%of carcinoma cells stained).Slug expression was correlated with clinicopathological parameters of IHCC patients.The patients were defined as short-term survivors if their survival time was<12 mo and as longterm survivors if their survival time was≥12 mo.RESULTS:Slug was not expressed in normal liver epi-thelium samples,lowly expressed in 15 tissue samples (10-,5+)and highly expressed in 21 tissue samples (16++;5+++)from IHCC patients.The survival rate of patients with a low slug expression was 33.3%(n =5)and 66.7%(n=10),respectively.The survival rate of patients with a high slug expression was 61.9% (n=13)and 38.1%(n=8),respectively(P=0.02).Lymph node metastasis was found in 4(26.7%)out of the 15 patients with a low slug expression and in 14(66.7%)out of the 21 patients with a high slug expression,respectively.The incidence rate of lymph node metastasis increased with the increasing slug expression level(P=0.003),and higher in patients with a high slug expression than in those with a low slug expression.Slug expression did not significantly correlate with the tumor size and stage or histologic grade,or with the gender and age of patients.CONCLUSION:Slug expression is a novel prognostic marker for IHCC with lymph node metastasis.
基金supported by the Natural Science Foundation of China(U20A2031)the Earmarked Fund for China Agricultural Research System(CARS-01).
文摘CONSTANS,CO-like,and TOC1(CCT)family genes play important roles in regulating heading date,which exerts a large impact on the regional and seasonal adaptation of rice.Previous studies have shown that Grain number,plant height,and heading date2(Ghd2)exhibits a negative response to drought stress by directly upregulating Rubisco activase and exerting a negative effect on heading date.However,the target gene of Ghd2 regulating heading date is still unknown.In this study,CO3 is identified by analyzing Ghd2 ChIP-seq data.Ghd2 activates CO3 expression by binding to the CO3 promoter through its CCT domain.EMSA experiments show that the motif CCACTA in the CO3 promoter was recognized by Ghd2.A comparison of the heading dates among plants with CO3 knocked out or overexpressed and double-mutants with Ghd2 overexpressed and CO3 knocked out shows that CO3 negatively and constantly regulates flowering by repressing the transcription of Ehd1,Hd3a,and RFT1.In addition,the target genes of CO3 are explored via a comprehensive analysis of DAP-seq and RNA-seq data.Taken together,these results suggest that Ghd2 directly binds to the downstream gene CO3,and the Ghd2eCO3 module constantly delays heading date via the Ehd1-mediated pathway.
文摘Alternative splicing （AS） is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence implicates splice isoforms in most if not all hallmarks of cancer, including growth, apoptosis, invasion and metastasis, angiogenesis, and metabolism. AS has important clinical implications since it can be manipulated therapeutically to treat cancer and represents a mechanism of resistance to therapy. In prostate cancer （PCa） AS also plays a prominent role and this review will summarize the current knowledge of alternatively spliced genes with important functional consequences. We will highlight accumulating evidence on AS of the components of the two critical pathways in PCa： androgen receptor （AR） and phosphoinositide 3-kinase （PI3K）. These observations together with data on dysregulation of splice factors in PCa suggest that AR and PI3K pathways may be interconnected with previously unappreciated splicing regulatory networks. In addition, we will discuss several lines of evidence implicating splicing regulation in the development of the castration resistance.
基金supported by the National Natural Science Foundation of China (No.30870507)partially supported by a grant from the Ministry of Science and Technology of China (No.2005CB522603)
文摘Objective： Id2 is a natural inhibitor of the basic helix-loop-helix（bHLH） transcription factors. Although it is well known that active ld2 prevents differentiation and promotes cell cycle progression and tumorigenesis, the molecular events that regulate Id2 activity remain to be investigated. Methods： Yeast two-hybrid, mammalian two-hybrid, GST-pulldown and immunoprecipitation （ColP） assays were used to screen and identify novel Id2 interactors. Luciferase assays were used to detect E47-mediated transcription activity. Colony formation and BrdU incorporation assays were used to determine cellular proliferation abilities. Northorn blot, western blot and quantitative PCR methods were used to measure gene expression levels. Electrophoretic mobility shift assays （EMSAs） were performed to investigate protein/DNA binding. Results： The LIM-only protein FHL2 （four-and-a-half-LIM-only protein 2） was identified to be a novel Id2 interactor. The HLH domain within Id2 is not required for its interaction with FHL2. FHL2 antagonizes the inhibitory effect of Id2 on the basic helix-loop-helix protein E47-mediated transcription. FHL2 prevents the formation of Id2-E47 heterdimer, thus releasing E47 to its target DNA and restoring its transcriptional activity. FHL2 expression was remarkably up-regulated during retinoic acid-induced differentiation of neuroblastoma cells, during which the expression of Id2 is opposite to that. Ectopic FHL2 expression in neuroblastoma cells markedly reduces the transcriptional and cell-cycle promoting functions of Id2. Conclusion： These results indicate that FHL2 is an important repressor of the oncogenic activity of Id2 in neuroblastoma cells.
基金Supported by In part by the 21st Century COE(Center Of Ex-cellence)Programs to Dr.Takenori Ochiaiby a Grant-in-Aid 18591453 to K.M from the Ministry of Education,Science,Sports and Culture of Japan
文摘AIM: To investigate a novel therapeutic strategy to target and suppress c-myc in human cancers using far up stream element (FUSE)-binding protein-interacting repressor (FIR).
基金supported by the National Natural Science Foundation of China(No.30870507)supported by a grant from the Ministry of Science and Technology of China(No.2010CB912802)
文摘Objective：FHL2 was previously identified to be a novel interacting factor of Id family proteins.The aim of this study was to investigate,the effects of FHL2 on Id1-mediated transcriptional regulation activity and its oncogenic activity in human breast cancer cells.Methods：Cell transfection was performed by Superfect reagent.Id1 stably overexpressed MCF-7 cells was cloned by G418 screening.The protein level of Id1 was detected by western blot analysis.Dual relative luciferase assays were used to measure the effect of E47-mediated transcriptional activity in MCF-7 human breast cancer cells.MTT assay was used to measure cell proliferation.Transwell assay was used to measure the invasive capacity of MCF-7 cancer cells.Results：The basic helix-loop-helix（bHLH） factor E47-mediated transcription activity was markedly repressed by Id1 in MCF-7 cells.This Id1-mediated repression was effectively antagonized by FHL2 transduction.Overexpression of Id1 markedly promoted the proliferation rate and invasive capacity of MCF-7 cells;however,these effects induced by Id1 were significantly suppressed by overexpression of FHL2 in cells.Conclusion：FHL2 can inhibit the proliferation and invasiveness of human breast cancer cells by repressing the functional activity of Id1.These findings provide the basis for further investigating the functional roles of FHL2-Id1 signaling in the carcinogenesis and development of human breast cancer.
基金supported by the National Natural Science Foundation of China(32002146 and 31872977)the China Postdoctoral Science Foundation(2020M671630)+3 种基金the Jiangsu Postdoctoral Science Foundation of China(2021K221B)to Chen Caithe Jiangsu Agriculture Science and Technology Innovation Fund,China[CX(19)2016]the Priority Academic Program Development of Jiangsu Higher Education Institutionsthe High-end Talent Support Program of Yangzhou University,China to Song Chengyi。
文摘Retrotransposons,a type of DNA fragment that can mobilize itself on genome,can generate genetic variations and develop for molecular markers based on the insertion polymorphism.Zinc finger proteins(ZNFs)are among the most abundant proteins in eukaryotic animals,and their functions are extraordinarily diverse and particularly important in gene regulation.In the current study,bioinformatic prediction was performed to screen for retrotransposon insertion polymorphisms(RIPs)in six ZNF genes(ZNF2,ZNF3,ZNF7,ZNF8,ZNF10 and ZNF12).Six RIPs in these ZNFs,including one short interspersed nuclear element(SINE)RIP in intron 1 and one long interspersed nuclear element 1(L1)RIP in intron 3 of ZNF2,one SINE RIP in 5′flanking region and one SINE RIP in intron 2 of ZNF3,one SINE RIP in 3′UTR of ZNF7 and one L1 RIP in intron 2 of ZNF12,were discovered and their presence was confirmed by PCR.The impact of the SINE RIP in the first intron of ZNF2,which is close to the core promoter of ZNF2,on the gene activity was investigated by dual-luciferase assay in three cell lines.Our results showed that the SINE insertion in the intron 1 of ZNF2 repressed the core promoter activity extremely significantly(P<0.01)in cervical cancer cells and porcine primary embryonic fibroblasts(HeLa and PEF),thus SINE may act as a repressor.This SINE RIP also significantly(P<0.05)affected the corrected back fat thickness in Yorkshire pigs.The corrected back fat thickness of individuals with SINE insertion in the first intron of ZNF2 was significantly(P<0.05)higher than that of individuals without SINE insertion.In summary,our data suggested that RIPs play important roles in the genetic variations of these ZNF genes and SINE RIP in the intron 1 of ZNF2 may provide a useful molecular marker for the screening of fat deposition in the pig breeding.
基金the National Natural Science Foundation of China(82072246,81871182)National key R&D plan(2016YFC0502304).
文摘L-Arginine is the precursor of nitric oxide(NO),a host immune effector against intracellular pathogens including Mycobacterium tuberculosis(M.tb).Pathogens including M.tb have evolved various strategies targeting arginine to block the production of NO for better survival and proliferation.However,L-arginine metabolism and regulation in Mycobacterium are poorly understood.Here,we report the identification of M.smegmatis MSMEG_1415(homolog of M.tb Rv2324)as an arginine-responsive transcriptional factor regulating the arginase pathway.In the absence of L-arginine,MSMEG_1415 acts as a repressor to inhibit the transcription of the roc(for arginine,ornithine catabolism)gene cluster,thereby switching off the arginase pathway.Treatment with L-arginine relieves the transcriptional inhibition of MSMEG_1415 on the roc gene cluster to activate the arginase pathway.Moreover,the L-arginine-MSMEG_1415 complex activates the transcription of the roc gene cluster by recognizing and binding a 15-bp palindrome motif,thereby preventing the excess accumulation of L-arginine in M.smegmatis.Physiologically,MSMEG_1415 confers mycobacteria resistance to starvation and fluoroquinolones exposure,suggestive of its important role in M.smegmatis persistence.The results uncover a unique regulatory mechanism of arginine metabolism in mycobacteria and identify M.tb Rv2324 as an attractive candidate target for the design of drugs against tuberculosis.
