PRC2 proteins EZH1 and EZH2 regulate postnatal hepatic maturation [RNA-Seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE118757 | GEO | 2019/03/01
REPOSITORIES: GEO
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Project description:The inability to derive fully functional cell types, such as hepatocytes, from stem cells may emanate from the lack of knowledge about mechanisms that underlie postnatal cell maturation. We characterized hepatic maturation during the postnatal day 14 (P14) to 2-month-old (M2) transition and found more than 3000 genes differentially expressed. Nearly half of such maturation genes have H3K27me3 at their promoters or gene bodies at P14 or M2. Genetic ablation of both PRC2 histone methyltransferases in perinatal livers causes hepatocytes to prematurely differentiate, expressing genes at P14 that would normally be induced later, by M2. Using srHC-seq, a new method to map sonication-resistant heterochromatin, we found that the H3K27me3+ prematurely upregulated genes have euchromatic promoters at P14. We also observed derepression of many non-hepatic lineage genes with euchromatic promoter H3K27me3-marking. Thus, Polycomb repression is used to restrain expression of late liver maturation genes and lineage inappropriate genes at euchromatic promoters.
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Project description:The inability to derive fully functional cell types, such as hepatocytes, from stem cells may emanate from the lack of knowledge about mechanisms that underlie postnatal cell maturation. We characterized hepatic maturation during the postnatal day 14 (P14) to 2-month-old (M2) transition and found more than 3000 genes differentially expressed. Nearly half of such maturation genes have H3K27me3 at their promoters or gene bodies at P14 or M2. Genetic ablation of both PRC2 histone methyltransferases in perinatal livers causes hepatocytes to prematurely differentiate, expressing genes at P14 that would normally be induced later, by M2. Using srHC-seq, a new method to map sonication-resistant heterochromatin, we found that the H3K27me3+ prematurely upregulated genes have euchromatic promoters at P14. We also observed derepression of many non-hepatic lineage genes with euchromatic promoter H3K27me3-marking. Thus, Polycomb repression is used to restrain expression of late liver maturation genes and lineage inappropriate genes at euchromatic promoters.
2019-03-01 | GSE119218 | GEO
Project description:The inability to derive fully functional cell types, such as hepatocytes, from stem cells may emanate from the lack of knowledge about mechanisms that underlie postnatal cell maturation. We characterized hepatic maturation during the postnatal day 14 (P14) to 2-month-old (M2) transition and found more than 3000 genes differentially expressed. Nearly half of such maturation genes have H3K27me3 at their promoters or gene bodies at P14 or M2. Genetic ablation of both PRC2 histone methyltransferases in perinatal livers causes hepatocytes to prematurely differentiate, expressing genes at P14 that would normally be induced later, by M2. Using srHC-seq, a new method to map sonication-resistant heterochromatin, we found that the H3K27me3+ prematurely upregulated genes have euchromatic promoters at P14. We also observed derepression of many non-hepatic lineage genes with euchromatic promoter H3K27me3-marking. Thus, Polycomb repression is used to restrain expression of late liver maturation genes and lineage inappropriate genes at euchromatic promoters.
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Project description:The functional and transcriptional maturation of neurons is a prolonged process that extends well beyond mitotic exit and terminal fate commitment of progenitors. The differentiation of cerebellar granule neurons (CGNs) in the postnatal mouse cerebellum provides a useful model to identify chromatin mechanisms that orchestrate temporal changes in transcription as postmitotic CGNs mature. Here we report that CGN maturation is associated with dynamic changes in the genomic distribution of histone H3 lysine 27 trimethylation (H3K27me3), a modification best known for its role in repressing alternative fates during cell specification. H3K27me3 is gained rapidly in newly postmitotic CGNs at progenitor-expressed genes that are repressed in neurons. H3K27me3 is lost more gradually at the promoters of a subset of neuronal genes that are transcriptionally induced upon CGN maturation. The loss of H3K27me3 is facilitated by the lysine demethylase KDM6B, and genes that are induced in maturing CGNs show impaired expression in the cerebellum of conditional KDM6B knockout mice. Genes that lose H3K27me3 gain H3K27 acetylation and binding of the pro-maturation ZIC1/2 transcription factors, suggesting that developmental loss of H3K27me3 may be required to permit the onset of transcriptional maturation. Interestingly, pharmacological inhibition of the H3K27 methyltransferase EZH2 in early postmitotic CGNs not only blocked the repression of progenitor genes but also impaired the induction of mature CGN genes. These data show that regulation of H3K27me3 functions in developing postmitotic neurons beyond the period of cell fate commitment to regulate the dynamics of gene expression programs that underlie functional neuronal maturation.
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Project description:The functional and transcriptional maturation of neurons is a prolonged process that extends well beyond mitotic exit and terminal fate commitment of progenitors. The differentiation of cerebellar granule neurons (CGNs) in the postnatal mouse cerebellum provides a useful model to identify chromatin mechanisms that orchestrate temporal changes in transcription as postmitotic CGNs mature. Here we report that CGN maturation is associated with dynamic changes in the genomic distribution of histone H3 lysine 27 trimethylation (H3K27me3), a modification best known for its role in repressing alternative fates during cell specification. H3K27me3 is gained rapidly in newly postmitotic CGNs at progenitor-expressed genes that are repressed in neurons. H3K27me3 is lost more gradually at the promoters of a subset of neuronal genes that are transcriptionally induced upon CGN maturation. The loss of H3K27me3 is facilitated by the lysine demethylase KDM6B, and genes that are induced in maturing CGNs show impaired expression in the cerebellum of conditional KDM6B knockout mice. Genes that lose H3K27me3 gain H3K27 acetylation and binding of the pro-maturation ZIC1/2 transcription factors, suggesting that developmental loss of H3K27me3 may be required to permit the onset of transcriptional maturation. Interestingly, pharmacological inhibition of the H3K27 methyltransferase EZH2 in early postmitotic CGNs not only blocked the repression of progenitor genes but also impaired the induction of mature CGN genes. These data show that regulation of H3K27me3 functions in developing postmitotic neurons beyond the period of cell fate commitment to regulate the dynamics of gene expression programs that underlie functional neuronal maturation.
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Project description:The functional and transcriptional maturation of neurons is a prolonged process that extends well beyond mitotic exit and terminal fate commitment of progenitors. The differentiation of cerebellar granule neurons (CGNs) in the postnatal mouse cerebellum provides a useful model to identify chromatin mechanisms that orchestrate temporal changes in transcription as postmitotic CGNs mature. Here we report that CGN maturation is associated with dynamic changes in the genomic distribution of histone H3 lysine 27 trimethylation (H3K27me3), a modification best known for its role in repressing alternative fates during cell specification. H3K27me3 is gained rapidly in newly postmitotic CGNs at progenitor-expressed genes that are repressed in neurons. H3K27me3 is lost more gradually at the promoters of a subset of neuronal genes that are transcriptionally induced upon CGN maturation. The loss of H3K27me3 is facilitated by the lysine demethylase KDM6B, and genes that are induced in maturing CGNs show impaired expression in the cerebellum of conditional KDM6B knockout mice. Genes that lose H3K27me3 gain H3K27 acetylation and binding of the pro-maturation ZIC1/2 transcription factors, suggesting that developmental loss of H3K27me3 may be required to permit the onset of transcriptional maturation. Interestingly, pharmacological inhibition of the H3K27 methyltransferase EZH2 in early postmitotic CGNs not only blocked the repression of progenitor genes but also impaired the induction of mature CGN genes. These data show that regulation of H3K27me3 functions in developing postmitotic neurons beyond the period of cell fate commitment to regulate the dynamics of gene expression programs that underlie functional neuronal maturation.
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