In the mammalian genome,most CpGs are methylated.However,CpGs within the CpG islands(CGIs)are largely unmethylated,which are important for gene expression regulation.The mechanism underlying the low methylation levels...In the mammalian genome,most CpGs are methylated.However,CpGs within the CpG islands(CGIs)are largely unmethylated,which are important for gene expression regulation.The mechanism underlying the low methylation levels at CGIs remains largely elusive.KDM2 proteins(KDM2A and KDM2B)are H3K36me2 demethylases known to bind specifically at CGIs.Here,we report that depletion of each or both KDM2 proteins,or mutation of all their JmjC domains that harbor the H3K36me2 demethylation activity,leads to an increase in DNA methylation at selective CGIs.The Kdm2a/2b double knockout shows a stronger increase in DNA methylation compared with the single mutant of Kdm2a or Kdm2b,indicating that KDM2A and KDM2B redundantly regulate DNA methylation at CGIs.In addition,the increase of CGI DNA methylation upon mutations of KDM2 proteins is associated with the chromatin environment.Our findings reveal that KDM2A and KDM2B function redundantly in regulating DNA methylation at a subset of CGIs in an H3K36me2 demethylation-dependent manner.展开更多
Tissue interactions play a crucial role in tooth development.Notably,extracellular vesicle-mediated interactions between the mandible and tooth germ are considered essential.Here,we revealed that mandible extracellula...Tissue interactions play a crucial role in tooth development.Notably,extracellular vesicle-mediated interactions between the mandible and tooth germ are considered essential.Here,we revealed that mandible extracellular vesicles could modulate the proliferation and differentiation of dental mesenchymal cells by regulating the histone demethylase KDM2B.Further investigation showed that mandible derived extracellular vesicles could deliver miR-206 to KDM2B,thereby regulating tooth development.An animal study demonstrated that the miR-206/KDM2B pathway affected tooth morphogenesis and mineralization after eight weeks of subcutaneous transplantation in nude mice.In conclusion,this study suggested that the mandible played a critical role in tooth morphogenesis and mineralization,which could be a potential therapeutic target for abnormal tooth development and an alternative model for tooth regeneration.展开更多
Intellectual disability(ID)is a condition characterized by cognitive impairment and difficulties in adaptive functioning.In our research,we identified two de novo mutations(c.955C>T and c.732C>A)at the KDM2A loc...Intellectual disability(ID)is a condition characterized by cognitive impairment and difficulties in adaptive functioning.In our research,we identified two de novo mutations(c.955C>T and c.732C>A)at the KDM2A locus in individuals with varying degrees of ID.In addition,by using the Gene4Denovo database,we discovered five additional cases of de novo mutations in KDM2A.The mutations we identified significantly decreased the expression of the KDM2A protein.To investigate the role of KDM2A in neural development,we used both 2D neural stem cell models and 3D cerebral organoids.Our findings demonstrated that the reduced expression of KDM2A impairs the proliferation of neural progenitor cells(NPCs),increases apoptosis,induces premature neuronal differentiation,and affects synapse maturation.Through ChIP-Seq analysis,we found that KDM2A exhibited binding to the transcription start site regions of genes involved in neurogenesis.In addition,the knockdown of KDM2A hindered H3K36me2 binding to the downstream regulatory elements of genes.By integrating ChIP-Seq and RNA-Seq data,we made a significant discovery of the core genes'remarkable enrichment in the MAPK signaling pathway.Importantly,this enrichment was specifically linked to the p38 MAPK pathway.Furthermore,disease enrichment analysis linked the differentially-expressed genes identified from RNA-Seq of NPCs and cerebral organoids to neurodevelopmental disorders such as ID,autism spectrum disorder,and schizophrenia.Overall,our findings suggest that KDM2A plays a crucial role in regulating the H3K36me2 modification of downstream genes,thereby modulating the MAPK signaling pathway and potentially impacting early brain development.展开更多
In reptiles,such as the red-eared slider turtle(Trachemys scripta elegans),gonadal sex determination is highly dependent on the environmental temperature during embryonic stages.This complex process,which leads to dif...In reptiles,such as the red-eared slider turtle(Trachemys scripta elegans),gonadal sex determination is highly dependent on the environmental temperature during embryonic stages.This complex process,which leads to differentiation into either testes or ovaries,is governed by the finely tuned expression of upstream genes,notably the testis-promoting gene Dmrt1 and the ovary-promoting gene Foxl2.Recent studies have identified epigenetic regulation as a crucial factor in testis development,with the H3K27me3 demethylase KDM6B being essential for Dmrt1 expression in T.s.elegans.However,whether KDM6B alone can induce testicular differentiation remains unclear.In this study,we found that overexpression of Kdm6b in T.s.elegans embryos induced the male development pathway,accompanied by a rapid increase in the gonadal expression of Dmrt1 at 31°C,a temperature typically resulting in female development.Notably,this sex reversal could be entirely rescued by Dmrt1 knockdown.These findings demonstrate that Kdm6b is sufficient for commitment to the male pathway,underscoring its role as a critical epigenetic regulator in the sex determination of the red-eared slider turtle.展开更多
基金supported by the National Natural Science Foundation of China(32070607)the National Key Research and Development Program of China(2020YFA0804000)the CAS Project for Young Scientists in Basic Research(YSBR-012).
文摘In the mammalian genome,most CpGs are methylated.However,CpGs within the CpG islands(CGIs)are largely unmethylated,which are important for gene expression regulation.The mechanism underlying the low methylation levels at CGIs remains largely elusive.KDM2 proteins(KDM2A and KDM2B)are H3K36me2 demethylases known to bind specifically at CGIs.Here,we report that depletion of each or both KDM2 proteins,or mutation of all their JmjC domains that harbor the H3K36me2 demethylation activity,leads to an increase in DNA methylation at selective CGIs.The Kdm2a/2b double knockout shows a stronger increase in DNA methylation compared with the single mutant of Kdm2a or Kdm2b,indicating that KDM2A and KDM2B redundantly regulate DNA methylation at CGIs.In addition,the increase of CGI DNA methylation upon mutations of KDM2 proteins is associated with the chromatin environment.Our findings reveal that KDM2A and KDM2B function redundantly in regulating DNA methylation at a subset of CGIs in an H3K36me2 demethylation-dependent manner.
基金supported by the National Natural Science Foundation of China(No.82071078,82370939)the Shaanxi Provincial High-level Talent Program and Young Talent Support Plan of Xi’an Jiaotong University.
文摘Tissue interactions play a crucial role in tooth development.Notably,extracellular vesicle-mediated interactions between the mandible and tooth germ are considered essential.Here,we revealed that mandible extracellular vesicles could modulate the proliferation and differentiation of dental mesenchymal cells by regulating the histone demethylase KDM2B.Further investigation showed that mandible derived extracellular vesicles could deliver miR-206 to KDM2B,thereby regulating tooth development.An animal study demonstrated that the miR-206/KDM2B pathway affected tooth morphogenesis and mineralization after eight weeks of subcutaneous transplantation in nude mice.In conclusion,this study suggested that the mandible played a critical role in tooth morphogenesis and mineralization,which could be a potential therapeutic target for abnormal tooth development and an alternative model for tooth regeneration.
基金supported by the National Natural Science Foundation of China(82022024,31970572,and 31871276)the National Key R&D Project of China(2016YFC1306000 and 2017YFC0908701)+3 种基金the Innovation-driven Project of Central South University(2020CX003)The Natural Science Foundation of Hunan Province(2023JJ40793)NIH grants(U01 MH122591,1U01MH116489,and 1R01MH110920)the Postgraduate Scientific Research Innovation Project of Hunan Province(CX20220320).
文摘Intellectual disability(ID)is a condition characterized by cognitive impairment and difficulties in adaptive functioning.In our research,we identified two de novo mutations(c.955C>T and c.732C>A)at the KDM2A locus in individuals with varying degrees of ID.In addition,by using the Gene4Denovo database,we discovered five additional cases of de novo mutations in KDM2A.The mutations we identified significantly decreased the expression of the KDM2A protein.To investigate the role of KDM2A in neural development,we used both 2D neural stem cell models and 3D cerebral organoids.Our findings demonstrated that the reduced expression of KDM2A impairs the proliferation of neural progenitor cells(NPCs),increases apoptosis,induces premature neuronal differentiation,and affects synapse maturation.Through ChIP-Seq analysis,we found that KDM2A exhibited binding to the transcription start site regions of genes involved in neurogenesis.In addition,the knockdown of KDM2A hindered H3K36me2 binding to the downstream regulatory elements of genes.By integrating ChIP-Seq and RNA-Seq data,we made a significant discovery of the core genes'remarkable enrichment in the MAPK signaling pathway.Importantly,this enrichment was specifically linked to the p38 MAPK pathway.Furthermore,disease enrichment analysis linked the differentially-expressed genes identified from RNA-Seq of NPCs and cerebral organoids to neurodevelopmental disorders such as ID,autism spectrum disorder,and schizophrenia.Overall,our findings suggest that KDM2A plays a crucial role in regulating the H3K36me2 modification of downstream genes,thereby modulating the MAPK signaling pathway and potentially impacting early brain development.
基金supported by the National Natural Science Foundation of China(32325049,U22A20529,32303000)Zhejiang Provincial Natural Science Foundation(LQ24C190009)+1 种基金Ningbo Natural Science Foundation(2022J192)Zhejiang Provincial Top Key Discipline of Biological Engineering(1741000592)。
文摘In reptiles,such as the red-eared slider turtle(Trachemys scripta elegans),gonadal sex determination is highly dependent on the environmental temperature during embryonic stages.This complex process,which leads to differentiation into either testes or ovaries,is governed by the finely tuned expression of upstream genes,notably the testis-promoting gene Dmrt1 and the ovary-promoting gene Foxl2.Recent studies have identified epigenetic regulation as a crucial factor in testis development,with the H3K27me3 demethylase KDM6B being essential for Dmrt1 expression in T.s.elegans.However,whether KDM6B alone can induce testicular differentiation remains unclear.In this study,we found that overexpression of Kdm6b in T.s.elegans embryos induced the male development pathway,accompanied by a rapid increase in the gonadal expression of Dmrt1 at 31°C,a temperature typically resulting in female development.Notably,this sex reversal could be entirely rescued by Dmrt1 knockdown.These findings demonstrate that Kdm6b is sufficient for commitment to the male pathway,underscoring its role as a critical epigenetic regulator in the sex determination of the red-eared slider turtle.
