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Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development

ABSTRACT: In the developing brain, neural progenitor cells (NPCs) switch the differentiation competency via changing gene expression profiles that are governed partly by epigenetic control such as histone modification, although the precise mechanism is unknown. Here we found that ESET/Setdb1/KMT1E, a histone H3 Lys-9 (H3K9) methyltransferase, was highly expressed at early stages of brain development but down-regulated over time, and that ablation of ESET led to decreased H3K9 trimethylation and misregulation of genes, resulting in severe brain defects and early lethality. In the mutant brain, endogenous retrotransposons were derepressed, and non-neural gene expression was activated. Furthermore, early neurogenesis was most severely impaired, while astrocyte formation was enhanced. We conclude that there is an epigenetic role of ESET in temporal and tissue-specific gene regulation in the developing brain. We used microarrays to identify genes up- or down- regulated when ESET is ablated in the dorsal telencephalon.

ORGANISM(S): Mus musculus

PROVIDER: GSE40296 | GEO | 2012/08/23

SECONDARY ACCESSION(S): PRJNA173430

REPOSITORIES: GEO

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Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development

Project description:In the developing brain, neural progenitor cells (NPCs) switch the differentiation competency via changing gene expression profiles that are governed partly by epigenetic control such as histone modification, although the precise mechanism is unknown. Here we found that ESET/Setdb1/KMT1E, a histone H3 Lys-9 (H3K9) methyltransferase, was highly expressed at early stages of brain development but down-regulated over time, and that ablation of ESET led to decreased H3K9 trimethylation and misregulation of genes, resulting in severe brain defects and early lethality. In the mutant brain, endogenous retrotransposons were derepressed, and non-neural gene expression was activated. Furthermore, early neurogenesis was most severely impaired, while astrocyte formation was enhanced. We conclude that there is an epigenetic role of ESET in temporal and tissue-specific gene regulation in the developing brain. We used microarrays to identify genes up- or down- regulated when ESET is ablated in the dorsal telencephalon. We used 3 WT and 3 cKO male E14.5 embryo for each analysis

2012-08-23 | E-GEOD-40296 | biostudies-arrayexpress

KMT1E Mediated H3K9 Methylation Is Required for the Maintenance of Embryonic Stem Cells by Repressing Trophectoderm Differentiation

Project description:Dynamic regulation of histone methylation by methyltransferases and demethylases plays a central role in regulating the fate of embryonic stem (ES) cells. The histone H3K9 methyltransferase KMT1E, formerly known as ESET or Setdb1, is essential to embryonic development as the ablation of the Setdb1 gene results in peri-implantation lethality and prevents the propagation of ES cells. However, Setdb1- null blastocysts do not display global changes in H3K9 methylation or DNA methylation, arguing against a genome- wide defect. Here we show that conditional deletion of the Setdb1 gene in ES cells results in the upregulation of lineage differentiation markers, especially trophectoderm-specific factors, similar to effects observed upon loss of Oct3/4 expression in ES cells. We demonstrate that KMT1E deficiency in ES cells leads to a decrease in histone H3K9 methylation at and derepression of trophoblast-associated genes such as Cdx2. Furthermore, we find genes that are derepressed upon Setdb1 deletion to overlap with known targets of polycomb mediated repression, suggesting that KMT1E mediated H3K9 methylation acts in concert with polycomb controlled H3K27 methylation. Our studies thus demonstrate an essential role for KMT1E in the control of developmentally regulated gene expression programs in ES cells. Analysis of KMT1E-deficiency in mouse embryonic stem cells using a Setdb1 conditional allele and tamoxifen-inducible Cre/loxP recombination

2011-04-15 | E-GEOD-28593 | biostudies-arrayexpress

Genome-wide maps of chromatin state in ESET+/+ and ESET-/- DP thymocytes

Project description:We generated genome-wide H3K9me3-state maps of DP thymocytes purified from ESET+/+ and ESET-/- mice by using next generation sequencing. Examination of H3K9 trimethylation in DP thymocytes purified from ESET+/+ and ESET-/- mice.

2016-07-03 | E-GEOD-73831 | biostudies-arrayexpress

KMT1E Mediated H3K9 Methylation Is Required for the Maintenance of Embryonic Stem Cells by Repressing Trophectoderm Differentiation

2011-04-15 | GSE28593 | GEO

Global gene-expression analyses of the Eset knock-down ES cells

Project description:The histone H3 lysine 9 (H3K9) methyltransferase Eset is an epigenetic regulator critical for the development of the inner cell mass (ICM). Although ICM-derived embryonic stem (ES) cells are normally unable to contribute to the trophectoderm (TE) in blastocysts, we find that depletion of Eset by shRNAs leads to differentiation with the formation of trophoblast-like cells and induction of trophoblast-associated gene expression. Using ChIP-seq analyses, we identified Eset target genes with Eset-dependent H3K9 trimethylation. We confirmed that genes that are preferentially expressed in the TE (Tcfap2a and Cdx2) are bound and repressed by Eset. Single cell PCR analysis shows that the expression of Cdx2 and Tcfap2a is also induced in Eset-depleted morula cells. Importantly, Eset-depleted cells can incorporate into the TE of a blastocyst and subsequently placental tissues. Co-immunoprecipitation and ChIP assays further demonstrates that Eset interacts with Oct4, which in turn recruits Eset to silence these trophoblast-associated genes. Our result suggests that Eset restricts the extraembryonic trophoblast lineage potential of pluripotent cells and links an epigenetic regulator to key cell fate decision through a pluripotency factor. We used microarrays to detail the global programme of gene expression of control shRNA knock-down ES cells and Eset shRNA knock-down ES cells

2009-11-04 | GSE17439 | GEO

Genome-wide mapping of Eset-binding sites and H3K9me3 state in mouse embryonic stem cells

2009-11-04 | GSE17642 | GEO

Genome-wide mapping of Eset-binding sites and H3K9me3 state in mouse embryonic stem cells

Project description:The histone H3 lysine 9 (H3K9) methyltransferase Eset is an epigenetic regulator critical for the development of the inner cell mass (ICM). Although ICM-derived embryonic stem (ES) cells are normally unable to contribute to the trophectoderm (TE) in blastocysts, we find that depletion of Eset by shRNAs leads to differentiation with the formation of trophoblast-like cells and induction of trophoblast-associated gene expression. Using ChIP-seq analyses, we identified Eset target genes with Eset-dependent H3K9 trimethylation. We confirmed that genes that are preferentially expressed in the TE (Tcfap2a and Cdx2) are bound and repressed by Eset. Single cell PCR analysis shows that the expression of Cdx2 and Tcfap2a is also induced in Eset-depleted morula cells. Importantly, Eset-depleted cells can incorporate into the TE of a blastocyst and subsequently placental tissues. Co-immunoprecipitation and ChIP assays further demonstrates that Eset interacts with Oct4, which in turn recruits Eset to silence these trophoblast-associated genes. Our result suggests that Eset restricts the extraembryonic trophoblast lineage potential of pluripotent cells and links an epigenetic regulator to key cell fate decision through a pluripotency factor. Keywords: Epigenetics Examine Eset-binding sites and compare the H3K9me3 state between Eset knockdown mouse ES cells and control knockdown mouse ES cells.

2009-11-04 | E-GEOD-17642 | biostudies-arrayexpress

Genome-wide maps of chromatin state in ESET+/+ and ESET-/- DP thymocytes

Project description:We generated genome-wide H3K9me3-state maps of DP thymocytes purified from ESET+/+ and ESET-/- mice by using next generation sequencing.

2016-01-01 | GSE73831 | GEO

Genome-wide analysis in ESET+/+ and ESET-/- thymocytes

Project description:Analysis of ESET deficient thymocytes at gene expression level. Each thymocyte developmental stage (preselected DP, postselected DP and CD4SP) was analysed. Total RNA obtained from isolated subpopulations of thymocytes from ESET+/+ and ESET-/- mice were analysed.

2016-07-03 | E-GEOD-73951 | biostudies-arrayexpress

Genome-wide analysis in ESET+/+ and ESET-/- thymocytes

Project description:Analysis of ESET deficient thymocytes at gene expression level. Each thymocyte developmental stage (preselected DP, postselected DP and CD4SP) was analysed.

2016-01-01 | GSE73951 | GEO

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