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H4K20me3 methyltransferase SMYD5 controls heterochromatin and chromosome integrity during embryonic stem cell differentiation [DNA-seq]

ABSTRACT: Epigenetic regulation of chromatin states is thought to control gene expression programs during lineage specification. However, the roles of repressive histone modifications such as trimethylated histone lysine 20 (H4K20me3) in development and genome stability are largely unknown. Here, we show that depletion of SMYD5, a H4K20me3 methyltransferase, leads to decreased H4K20me3 and H3K9me3 ChIP-Seq levels, and de-repression of endogenous LTR/LINE elements during differentiation. SMYD5 depletion results in chromosomal aberrations and the formation of transformed cells that exhibit decreased H4K20me3 and H3K9me3 levels and an expression signature consistent with multiple human cancers. Moreover, dysregulated gene expression in SMYD5 cancer cells is associated with LTR/ERV elements and decreased H4K20me3. These findings implicate an important role for SMYD5 in maintaining chromosome integrity by regulating heterochromatin and repressing endogenous repetitive DNA elements during differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE95094 | GEO | 2018/03/14

REPOSITORIES: GEO

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H4K20me3 methyltransferase SMYD5 controls heterochromatin and chromosome integrity during embryonic stem cell differentiation

Project description:Epigenetic regulation of chromatin states is thought to control gene expression programs during lineage specification. However, the roles of repressive histone modifications such as trimethylated histone lysine 20 (H4K20me3) in development and genome stability are largely unknown. Here, we show that depletion of SMYD5, a H4K20me3 methyltransferase, leads to decreased H4K20me3 and H3K9me3 ChIP-Seq levels, and de-repression of endogenous LTR/LINE elements during differentiation. SMYD5 depletion results in chromosomal aberrations and the formation of transformed cells that exhibit decreased H4K20me3 and H3K9me3 levels and an expression signature consistent with multiple human cancers. Moreover, dysregulated gene expression in SMYD5 cancer cells is associated with LTR/ERV elements and decreased H4K20me3. These findings implicate an important role for SMYD5 in maintaining chromosome integrity by regulating heterochromatin and repressing endogenous repetitive DNA elements during differentiation.

2018-02-13 | GSE94955 | GEO

SMYD5 regulates H4K20me3-marked heterochromatin to safeguard ES cell self-renewal and prevent spurious differentiation [RNA-Seq]

Project description:Epigenetic regulation of chromatin states is thought to control the self-renewal and differentiation of embryonic stem (ES) cells. However, the roles of repressive histone modifications such as trimethylated histone lysine 20 (H4K20me3) in pluripotency and development are largely unknown. Here, we show that the histone lysine methyltransferase SMYD5 mediates H4K20me3 at heterochromatin regions. Depletion of SMYD5 leads to compromised self-renewal, including dysregulated expression of OCT4 targets, and perturbed differentiation. SMYD5 bound regions are enriched with repetitive DNA elements. Knockdown of SMYD5 results in a global decrease of H4K20me3 levels, a redistribution of heterochromatin constituents including H3K9me3/2, G9a, and HP1α, and de-repression of endogenous retroelements. A loss of SMYD5-dependent silencing of heterochromatin nearby genic regions leads to upregulated expression of lineage-specific genes, thus contributing to the decreased self-renewal and accelerated differentiation of SMYD5-depeleted ES cells. Altogether, these findings implicate a role for SMYD5 in regulating ES cell self-renewal and H4K20me3-marked heterochromatin.

2017-06-12 | GSE94085 | GEO

SMYD5 regulates H4K20me3-marked heterochromatin to safeguard ES cell self-renewal and prevent spurious differentiation [ChIP-Seq]

2017-06-12 | GSE94033 | GEO

H4K20me3 co-localizes with activating histone modifications at transcriptionally dynamic regions in embryonic stem cells

Project description:Bivalent chromatin domains consisting of the activating histone 3 lysine 4 trimethylation (H3K4me3) and repressive histone 3 lysine 27 trimethylation (H3K27me3) histone modifications are enriched at developmental genes that are repressed in embryonic stem cells but active during differentiation. However, it is unknown whether another repressive histone modification, histone 4 lysine 20 trimethylation (H4K20me3), co-localizes with activating histone marks in ES cells. Here, we describe the previously uncharacterized coupling of the repressive H4K20me3 heterochromatin mark with the activating histone modifications H3K4me3 and histone 3 lysine 36 trimethylation (H3K36me3), and transcriptional machinery (RNA polymerase II; RNAPII), in ES cells. These newly described bivalent domains consisting of H3K4me3/H4K20me3 are predominantly located in intergenic regions and near transcriptional start sites of active genes, while H3K36me3/H4K20me3 are located in intergenic regions and within gene body regions of active genes. Global sequential ChIP, also termed reChIP-Seq, confirmed the simultaneous presence of H3K4me3 and H4K20me3 at the same genomic regions in ES cells. Genes containing H3K4me3/H4K20me3 exhibit decreased RNAPII pausing and are poised for deactivation of RNAPII binding during differentiation relative to H3K4me3 marked genes. An evaluation of transcription factor (TF) binding motif enrichment revealed that DNA sequence may play a role in shaping the landscape of these novel bivalent domains. Moreover, H3K4me3/H4K20me3 and H3K36me3/H4K20me3 bound regions are enriched with repetitive LINE and LTR elements.

2018-06-18 | GSE115907 | GEO

SMYD5 catalyzes histone H3 lysine 36 trimethylation at promoters

Project description:Histone mark, one carrier of epigenetic information, regulates the gene expression in cells. Studies have shown that H3K36me3 is mainly catalyzed by SETD2 to be deposited at gene body regions in mammalian cells. Here, we profile the distributions of H3K36me3 in native cells and uncover that H3K36me3 is also enriched at the promoters beyond the gene body regions. We identify SMYD5 as one methyltransferase responsible for the enrichment of H3K36me3 at promoters. Through RNA polymerase II, SMYD5 is recruited to chromatin to regulate H3K36me3 and gene expression. The enzymatic activity of SMYD5 is dependent on its C-terminal glutamic acid rich domain. Depletion of C-terminal domain reduces the reestablishment of H3K36me3 at promoters when Smyd5 is over-expressed in Smyd5 knockout cells. Furthermore, elevated Smyd5 expression contributes to the tumorigenesis of liver hepatocellular carcinoma. Together, our study reveals SMYD5 as the H3K36me3 methyltransferase at promoters to regulate the gene expression, providing important insights into the localization and function of H3K36me3.

2022-04-26 | GSE184894 | GEO

Chip-chip from MEF cells with H3ac, H4ac, H4K20me1, H3K27me3, H3K9me3, H4K20me3, H3K4me2, H3K4me3 and H3K9ac

Project description:Genome wide chromatin maps have shown that spreading repressive histone modifications such as H3K9me3 and H4K20me3 are present on pericentromeric and telomeric repeats and on the inactive X chromosome where H3K27me3 or H3K9me3 alternately modify megabasepair sized domains. However, only a few regions along an autosome of which Homeobox gene clusters are notable examples, have been shown to display spreading of repressive histone modifications. Here we present a ChIP-Chip map of repressive and active histone modifications along mouse Chr.17 in embryonic, fibroblast cells. Our results show that the majority of H3K27me3 modifications form BLOCs rather than focal peaks. H3K27me3 BLOCs modify silent genes of all types and their flanking intergenic regions, indicating a negative correlation between H3K27me3 and transcription. However, non-transcribed gene-poor regions also lacked H3K27me3. We therefore performed a low resolution analysis of whole mouse Chr.17 which revealed that H3K27me3 specifically marks megabasepair sized domains that are enriched for genes, SINEs and active histone modifications. These genic H3K27me3 domains alternate with similar sized gene-poor domains that are deficient in active histone modifications, but enriched for LINE and LTR transposons as well as H3K9me3 and H4K20me3. Thus, a mouse autosome can be seen to contain alternating chromatin bands that predominantly separate genes from one retrotransposons class, which could offer unique chromatin compartments for the specific regulation of genes or the silencing of transposons. Keywords: Chip-chip, chromosome 17 wide unbiased mapping unbiased mapping of several histone modifications on chromosome 17 in two independent MEF cell lines

2008-11-23 | E-GEOD-11335 | biostudies-arrayexpress

SMYD5 regulates mRNA translation to promote gastric adenocarcinoma (GAC)

Project description:Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis. However, whether analogous pathologic epigenetic mechanisms act directly on the ribosome to advance oncogenesis is unclear. Here we find that trimethylation of the core ribosomal protein L40 at lysine 22 (rpL40K22me3) by the lysine methyltransferase (KMT) SMYD5 regulates mRNA translation output to promote gastric adenocarcinoma (GAC) malignant progression with lethal peritoneal ascites. A biochemical-proteomic strategy identifies the mono-ubiquitin fusion protein partner rpL40 as the principal physiologic substrate of SMYD5 across diverse samples. Inhibiting the SMYD5-rpL40K22me3 axis in GAC cell lines reprograms protein synthesis to attenuate oncogenic gene expression signatures. SMYD5 and rpL40K22me3 are upregulated in GAC patient samples and negatively correlate with clinical outcomes. SMYD5 ablation in vivo in familial and sporadic mouse models of malignant GAC blocks metastatic disease including peritoneal carcinomatosis (PC). Suppressing SMYD5 methylation of rpL40 inhibits human cancer cell and patient-derived GAC xenograft growth and renders them hypersensitive to PI3K/mTOR inhibitors. Finally, combining SMYD5 depletion with PI3K/mTOR inhibition and CAR-T administration cures an otherwise lethal in vivo mouse model of aggressive GAC-derived PC. Together, our work uncovers a ribosome-based epigenetic mechanism that facilitates evolution of malignant GAC and nominates SMYD5 targeting as part of a potential cornerstone combination therapy to treat a deadly cancer.

2024-03-01 | GSE238257 | GEO

H4K20me3 methyltransferase SUV420H2 shapes the chromatin landscape of pluripotent embryonic stem cells

Project description:Heterochromatin, which is a densely packed chromatin state that is transcriptionally silent, is a critical regulator of gene expression. However, it is unclear how the repressive histone modification, H4K20me3, or the histone methyltransferase, SUV420H2, regulate embryonic stem (ES) cell fate by patterning the epigenetic landscape. Here, we report that depletion of SUV420H2 leads to a near complete loss of H4K20me3 genome-wide, dysregulated gene expression, and delayed ES cell differentiation. SUV420H2-bound regions are enriched with repetitive DNA elements, which are de-repressed in SUV420H2 knockout ES cells. Moreover, SUV420H2 regulation of H4K20me3-marked heterochromatin controls chromatin architecture, including fine-scale interactions between gene regulatory elements in pluripotent ES cells. SUV420H2 plays a critical role in stabilizing the three-dimensional (3D) chromatin landscape of ES cells, where loss of SUV420H2 results in A/B compartment switching, perturbed chromatin insulation, and altered chromatin interactions of pericentric heterochromatin, indicative of localized decondensation. In addition, depletion of SUV420H2 resulted in compromised interactions between H4K20me3 and gene regulatory regions. Together, these findings describe a novel role for SUV420H2 in regulating the chromatin landscape of ES cells.

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SMYD5 regulates H4K20me3-marked heterochromatin to safeguard ES cell self-renewal and prevent spurious differentiation

Project description:SMYD5 regulates H4K20me3-marked heterochromatin to safeguard ES cell self-renewal and prevent spurious differentiation

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DNMT1 reads heterochromatic H4K20me3 to reinforce DNA methylation of transposons

Project description:DNA methylation and trimethylated histone H4K20 (H4K20me3) constitute two important epigenetic mechanisms that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two modifications crosstalk. Here, we report the specific readout of heterochromatin marks H4K20me3 by the first bromo-adjacent-homology (BAH1) domain of maintenance DNA methyltransferase DNMT1. Engagement of BAH1-H4K20me3 ensures heterochromatin targeting of DNMT1, and cooperates with the previously reported readout of H3K9me3/H3 ubiquitination by the RFTS domain to allosterically stimulate DNMT1’s activity at both global and focal levels. Interplay between RFTS and BAH1 domains profoundly impacts the maintenance of DNA methylation and genomic resistance to radiation damage. Together, our study provides a heterochromatin-regulated model for DNMT1 in which multivalent recognition of repressive histone modifications by DNMT1 directly influence the cellular landscape of DNA methylation and genomic stability.

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