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A multivalent signal-transducing model for the DNMT1-mediated maintenance DNA methylation

ABSTRACT: Heterochromatin-specific histone modifications frequently coexist with mammalian DNA methylation to orchestrate a repressive chromatin state. However, it remains elusive how these epigenetic modifications crosstalk. Here, we report that the first bromoadjacent homology (BAH1) domain and the replication foci targeting sequence (RFTS) of maintenance DNA methyltransferase DNMT1 function as readers for H4K20me3 and H3K9me3, respectively. Engagements of H4K20me3 by BAH1 and H3K9me3 by RFTS ensure localization of DNMT1 to heterochromatin in cells, and cooperate with the RFTS-ubiquitination readout to allosterically stimulate DNMT1 s methylation activity at both global and focal levels. Strikingly, there is intramolecular crosstalk between the RFTS and BAH1 domains, which profoundly impacts the maintenance of DNA methylation and genomic resistance to radiation damage. Together, our study reveals an all-in-one model for DNMT1 in which repressive histone modifications directly influence the cellular landscape of DNA methylation and genomic stability, a process implicative of the DNMT1-related pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE145698 | GEO | 2020/07/27

REPOSITORIES: GEO

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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.

2021-12-31 | GSE162141 | GEO

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

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.

2018-03-14 | GSE95094 | GEO

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

Aberrant heterochromatic foci are associated to deregulation of the GMCL1 gene in CH1 lymphoma B cells

Project description:Chromosome 1 pericentric heterochromatin rearrangements : potent drivers of nuclear architecture perturbations and gene deregulation in human B cell lymphoma Epigenetic perturbations are increasingly described in cancer cells where they are thought to contribute to deregulated gene expression and genome instability. Here, we report the first evidence, that a distinct category of chromosomal translocation observed in human tumours â those targeting 1q12 satellite DNA - can directly mediate such perturbations by promoting the formation of aberrant heterochromatic foci (aHCF). By detailed investigations of a 1q12 translocation to chromosome 2p, in a case of human B cell lymphoma, aberrant aHCF were shown to be localised to the nuclear periphery and to arise as a consequence of long range âpairingâ between the translocated 1q12 and chromosome 2 centromeric regions. Remarkably, adjacent 2p sequences showed increased levels of repressive histone modifications, including H4K20me3 and H3K9me3, and were bound by HP1. aHCF were associated to aberrant spatial localisation and deregulated expression of a novel 2p gene (GMCL1) that was found to have prognostic impact in B cell lymphoma. Thus constitutive heterochromatin rearrangements can contribute to tumourigenesis by perturbing gene expression by via long range epigenetic mechanisms. The formation of aberrant heterochromatic foci, coupled to abnormal enrichment of adjacent 2p sequences in repressive heterochromatin marks (H4K20me3, H3K9me3 and HP1), delayed replication and repositioning of the rearranged chromosome 2 to the nuclear periphery, could be associated to altered gene expression of at least those genes brought into close proximity to heterochromatin. To assess this question, global gene expression profiling was performed in the lymphoma B cells presenting the aberrant heterochromatin foci (CH1), treated or not with the histone deacetylase inhibitor, trichostatin A.

2010-03-23 | E-GEOD-20666 | biostudies-arrayexpress

Relationship between gene body DNA methylation and intragenic H3K9me3 and H3K36me3 chromatin marks

Project description:Analysis of cross talk of epigenetic marks in HBEC by using tilling arrays chr19. In Human Bronchial epithelia cells (HBEC), H3K9me3, H4K20me3, H3K4me3, H3K27me3, H3K36me3 and DNA methylation were profiled. In these cells, DNA methylation status was analyzed by MIRA and UnmethylCollector (UMC). Study of epigenetic changes in HCT116 DNMT1-/- and DNMT3b -/- (HCT116-DKO) in comparison to intact HCT116. In HCT116 and HCT116-DKO, H3K9me3, H3K36me3 and DNA methylation were profiled. In these cells, DNA methylation status was analyzed by MIRA. Analysis of epigenetic changes caused by siRNA for SED2 transcript in HBEC. In HBEC and SETD2 siRNA HBEC, H3K36me3 and DNA methylation were profiled. In these cells, DNA methylation status was analyzed by MIRA. Comapre DNA methylation and other histone modification marks

2011-03-31 | E-GEOD-26040 | biostudies-arrayexpress

PRMT5-mediated histone H4 arginine-3 symmetrical dimethylation marks chromatin at G+C-rich regions of the mouse genome.

Project description:Symmetrical dimethylation on arginine-3 of histone H4 (H4R3me2s) has been reported to occur at several repressed genes, but its specific regulation and genomic distribution remained unclear. Here, we show that the type-II protein arginine methyltransferase PRMT5 controls H4R3me2s in mouse embryonic fibroblasts (MEFs). In these differentiated cells, we find that the genome-wide pattern of H4R3me2s is highly similar to that in embryonic stem cells. In both the cell types, H4R3me2s peaks are detected predominantly at G + C-rich regions. Promoters are consistently marked by H4R3me2s, independently of transcriptional activity. Remarkably, H4R3me2s is mono-allelic at imprinting control regions (ICRs), at which it marks the same parental allele as H3K9me3, H4K20me3 and DNA methylation. These repressive chromatin modifications are regulated independently, however, since PRMT5-depletion in MEFs resulted in loss of H4R3me2s, without affecting H3K9me3, H4K20me3 or DNA methylation. Conversely, depletion of ESET (KMT1E) or SUV420H1/H2 (KMT5B/C) affected H3K9me3 and H4K20me3, respectively, without altering H4R3me2s at ICRs. Combined, our data indicate that PRMT5-mediated H4R3me2s uniquely marks the mammalian genome, mostly at G + C-rich regions, and independently from transcriptional activity or chromatin repression. Furthermore, comparative bioinformatics analyses suggest a putative role of PRMT5-mediated H4R3me2s in chromatin configuration in the nucleus. High throughput sequencing data from H4R3me2s native ChIP samples from mouse embryonic stem cells and fibroblasts were generated using Illumina Hi-seq 2000.

2013-10-04 | E-GEOD-37604 | biostudies-arrayexpress

LSD1 Prevents Aberrant Heterochromatin Formation in Neurospora crassa

Project description:Heterochromatin is a specialized form of chromatin that restricts access to DNA and inhibits genetic processes, including transcription and recombination. In Neurospora crassa, constitutive heterochromatin is characterized by trimethylation of lysine 9 on histone H3, hypoacetylation of histones, and DNA methylation. Here we explore whether the conserved histone demethylase, lysine-specific demethylase 1 (LSD1), regulates heterochromatin in Neurospora, and if so, how. Though LSD1 is implicated in heterochromatin regulation, its function is inconsistent across different systems; orthologs of LSD1 have been shown to either promote or antagonize heterochromatin expansion by removing H3K4me or H3K9me respectively. We identify three members of the Neurospora LSD complex (LSDC): LSD1, PHF1, and BDP-1, and strains deficient for any exhibit variable spreading of heterochromatin and establishment of new heterochromatin domains dispersed across the genome. Heterochromatin establishment outside of canonical domains in Neurospora share the unusual characteristic of DNA methylation-dependent H3K9me3; typically, H3K9me3 establishment is independent of DNA methylation. Consistent with this, the hyper-H3K9me3 phenotype of LSD1 knock-out strains is dependent on the presence of DNA methylation, as well as HCHC-mediated histone deacetylation, suggesting spreading is dependent on some feedback mechanism. Altogether, our results suggest LSD1 works in opposition to HCHC to maintain proper heterochromatin boundaries.

2021-07-21 | PXD017300 | Pride

H3K64me3 and H3K9me3 profiling at promoters in mouse embryonic stem cells

Project description:Histone modifications are central to the regulation of all DNA-dependent processes but the repertoire of known modifications is far from complete. Lysine 64 of Histone H3 (H3K64) lies within the globular domain of H3 at a structurally important position within the nucleosome. We identify tri-methylation of H3K64 (H3K64me3) as a modification enriched in pericentric heterochromatin and associated with repeated sequences and transcriptionally inactive genomic regions. Interestingly, the pericentric enrichment of H3K64me3 depends on the Suv39h methyltransferases. Further, we show that this newly identified mark is dynamically regulated during the two major epigenetic reprogramming events in mammals. In primordial germ cells (PGCs) H3K64me3 is present at the time of specification, but disappears transiently during germline reprogramming. In the early mouse embryo it is inherited exclusively through the maternal germline and specifically enriched in heterochromatic regions of the maternal pronucleus. Subsequently the modification is rapidly removed from the maternal chromatin suggesting an important role for H3K64me3 turnover in development. Taken together, our findings firmly establish H3K64me3 as a novel histone modification mark of repressive chromatin, which displays crosstalk to the Suv39 pathway and is dynamically reprogrammed during development. We hypothesize that methylation of this lysine helps to 'secure' the nucleosome and perhaps the surrounding heterochromatin, in an appropriately repressed state during development. Keywords: ChIP-chip, embryonic stem cells, H3K64me3, H3K9me3, heterochromatin ChIP-chip experiments were performed with four independent biological replicates for H3K64me3 and two independent replicates for H3K9me3. For each condition hybridizations include a dye-swap experiment.

2010-05-16 | E-GEOD-16185 | biostudies-arrayexpress

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