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GLP is critical for oogenesis exhibiting a G9A-independent role in transcriptional repression

ABSTRACT: GLP (EHMT1) functions as an H3K9me1 and H3K9me2 methyltransferase through its reportedly obligatory dimerization with G9A (EHMT2). Here, we investigated the role of GLP in oocyte and embryo development in comparison to G9A using oocyte-specific conditional knockout mouse models (G9a cKO, Glp cKO, G9a-Glp cDKO). Loss of GLP in oogenesis severely impairs oocyte maturation, fertilization and embryo development, resulting in lethality before embryonic day E12.5. In contrast, loss of G9A has a milder effect with a proportion of embryos producing viable offspring. The Glp cKO also showed loss of G9A protein and, hence, was phenotypically very similar to the G9a-Glp cDKO. H3K9me2 was equally depleted in all cKO genotypes, whereas H3K9me1 was decreased only in Glp cKO and G9a-Glp cDKO oocytes. Furthermore, the transcriptome, DNA methylome and proteome were markedly more affected in G9a-Glp cDKO than G9a cKO oocytes, demonstrating that in the absence of GLP there are widespread epigenetic and gene expression changes in the oocyte independent of H3K9me2. Gene dysregulation with coupled changes in DNA methylation suggest localised loss of chromatin repression, resulting in upregulated protein expression. Together, our findings demonstrate that GLP can function independently of G9A in the oocyte and is required for oocyte developmental competence.

ORGANISM(S): Mus musculus

PROVIDER: GSE191026 | GEO | 2022/12/02

REPOSITORIES: GEO

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Multi-omics analyses demonstrate a critical role for EHMT1 methyltransferase in transcriptionalrepression during oogenesis

Project description:EHMT1 (also known as GLP) is a multifunctional protein, best known for its role as an H3K9me1 and H3K9me2 methyltransferase through its reportedly obligatory dimerization with EHMT2 (also known as G9A). Here, we investigated the role of EHMT1 in the oocyte in comparison to EHMT2 using oocyte-specific conditional knockout mouse models (Ehmt2 cKO, Ehmt1cKO, Ehmt1/2 cDKO), with ablation from the early phase of oocyte growth. Loss of EHMT1 in Ehmt1 cKO and Ehmt1/2 cDKO oocytes recapitulated meiotic defects observed in the Ehmt2 cKO; however, there was a significant impairment in oocyte maturation and developmental competence in Ehmt1 cKO and Ehmt1/2 cDKO oocytes beyond that observed in the Ehmt2cKO. Consequently, loss of EHMT1 in oogenesis results, upon fertilization, in mid-gestation embryonic lethality. To identify H3K9 methylation and other meaningful biological changes in each mutant to explore the molecular functions of EHMT1 and EHMT2, we performed immunofluorescence imaging, multi-omics sequencing, and mass spectrometry (MS)–based proteome analyses in cKO oocytes. Although H3K9me1 was depleted only upon loss of EHMT1, H3K9me2 was decreased, and H3K9me2-enriched domains were eliminated equally upon loss of EHMT1 or EHMT2. Furthermore, there were more significant changes in the transcriptome, DNA methylome, and proteome in Ehmt1/2 cDKO than Ehmt2 cKO oocytes, withtranscriptional derepression leading to increased protein abundance and local changes in genic DNA methylation in Ehmt1/2 cDKO oocytes. Together, our findings suggest that EHMT1 contributes to local transcriptional repression in the oocyte, partially independent of EHMT2, and is critical for oogenesis and oocyte developmental competence

2023-01-30 | PXD030265 | Pride

A role for Widely Interspaced Zinc finger (WIZ) in retention of the G9a methyltransferase on chromatin

Project description:G9a and GLP lysine methyltransferases form a heterodimeric complex that is responsible for the bulk of cellular mono- and di-methylation on histone H3 lysine 9 (H3K9me1/me2). Widely Interspaced Zinc finger (WIZ) associates with the G9a/GLP protein complex, but its role in lysine methylation is poorly defined. Here, we show that WIZ regulates global H3K9me2 levels through a mechanism that involves retention of G9a on chromatin. We also show that WIZ-mediated chromatin loss of G9a/GLP results in altered gene expression and protein-protein interactions that are distinguishable from that of using a molecule-induced enzymatic inhibitor towards G9a/GLP – thus providing evidence that the G9a/GLP/WIZ complex has unique functions when bound to chromatin that are independent of the H3K9me2 mark DMSO, UNC0638, NS, and siWIZ treatments to HEK293T cells, assessing G9a and H3K9me2 localization, each performed in duplicate, plus one input control for each cell condition. 30 samples total.

2015-09-03 | E-GEOD-67317 | biostudies-arrayexpress

A role for Widely Interspaced Zinc finger (WIZ) in retention of the G9a methyltransferase on chromatin

2015-09-03 | GSE67317 | GEO

Unexpected distinct roles of the related histone H3 lysine 9 methyltransferases G9a and G9a-Like Protein in myoblasts

Project description:Lysine methyltransferases G9a and GLP (G9a- Like Protein) form functional heterodimeric complexes that establish mono- and dimethylation on histone H3 lysine 9 (H3K9me1, H3K9me2) in euchromatin. Here we describe unexpected opposite individual roles for G9a and GLP during skeletal muscle terminal differentiation. Indeed, gain- or loss-of-function assays in myoblasts showed that in consistency with previous reports that G9a inhibits terminal differentiation. But GLP plays a more complicated role in muscle differentiation since both knockdown and overexpression inhibits terminal differentiation. Unexpectedly, in contrast to G9a, we show that GLP overexpression promotes abnormal expression of muscle differentiationspecific genes in proliferating myoblasts. Transcriptomic analysis indicates that G9a and GLP regulate different sets of genes. GLP, but not G9a, inhibits at the transcriptional level proteasome subunit-encoding genes resulting in an inhibition of the proteasome activities. Subsequently, GLP, but not G9a, overexpression stabilizes MyoD that is likely to be responsible for muscle markers expression in proliferating myoblasts.

2016-02-01 | GSE72626 | GEO

Investigation of the role of histone modification propagating activity of GLP

Project description:We use ChIP-Seq and RNA-Seq technology to profile the H3K9me2 modification and transcription under different conditions of GLP activity. GLP and G9a are major H3K9 dimethylases, and are essential for mouse early embryonic development. Here we report that GLP and G9a possess intrinsic histone methylation propagating activities. The histone methyltransferase activities of GLP and G9a are stimulated by neighboring nucleosomes pre-methylated at H3K9. These stimulation events function in cis and are dependent on H3K9 methylation binding activities of ankyrin repeats domains in GLP and G9a. In mouse embryonic stem cells (ESCs) harboring a mutant GLP lacking H3K9 methylation propagating activity, pluripotent genes display a delayed kinetics in establishing H3K9 methylation and gene silencing during differentiation. Disruption of the H3K9 methylation propagating activity of GLP in mice causes growth retardation of the embryos, ossification defects of calvaria and early postnatal lethality. We propose that GLP¡¯s ability to rapidly propagate H3K9 methylation is required for efficient gene silencing during programmed cell fate transition. H3K9me2 and H3K9me1 are ChIPped and sequenced in WT mESC and GLP-mutant mESCs, and RNA-Seq was done for those cells as well.

2015-01-20 | E-GEOD-54412 | biostudies-arrayexpress

Identification of proteins stably associated with G9a/GLP (EHMT2/EHMT1) complex of histone methyltransferases

Project description:G9a (EHMT2) and the G9a-like protein GLP (EHMT1) form a stable G9a/GLP heterodimer in embryonic stem cells and function cooperatively to establish and maintain the abundant repressive H3K9me2 modification, in addition to modifying several non-histone proteins. The G9a-dependent H3K9me2 is implicated in lineage-specific gene silencing and covers large chromosomal domains. While the mechanism of H3K9me2maintenance by G9a/GLP is known, how new patterns of this modification are established is not well understood. With this in mind, we used FLAG affinity purification of G9a under two different stringency conditions (150 and 300 mM NaCl) coupled with mass spectrometry to identify proteins stably associated with G9a/GLP, which could serve as potential recruiters of the complex to unmodified chromatin.

2016-03-16 | PXD003466 | Pride

Regulation of mammalian 3D genome organization and histone H3K9 dimethylation by H3K9 methyltransferases

Project description:Histone H3 lysine 9 dimethylation (H3K9me2) is a highly conserved silencing epigenetic mark. Chromatin marked with H3K9me2 forms large domains in mammalian cells and overlaps well with lamina-associated domains and the B compartment defined by Hi-C. However, the role of H3K9me2 in 3-dimensional (3D) genome organization remains unclear. We investigated genome-wide H3K9me2 distribution, transcriptome, and 3D genome organization in mouse embryonic stem cells following the inhibition or depletion of five H3K9 methyltransferases (MTases): G9a, GLP, SETDB1, SUV39H1, and SUV39H2. H3K9me2 was regulated by all five MTases; however, H3K9me2 and transcription in the A and B compartments were regulated by different MTases. H3K9me2 in A compartments was primarily regulated by G9a/GLP and SETDB1, while H3K9me2 in the B compartments was regulated by all five MTases. Furthermore, decreased H3K9me2 correlated with changes to the more active compartmental state that accompanied transcriptional activation.

2021-08-05 | PXD024756 | Pride

G9a/GLP-dependent H3K9me2 patterning alters chromatin structure at CpG islands in hematopoietic progenitors.

Project description:We profiled chromatin accessibility across the genome of HSPCs treated with either a small molecule inhibitor of G9a/GLP or DMSO. We observed that chromatin accessibility is dramatically altered at the regions of H3K9me2 nucleation. We have characterized the regions of H3K9me2 nucleation, revealing that H3K9me2 is nucleated in HSPCs at CpG islands (CGIs) and CGI-like sequences across the genome. Our analysis furthermore revealed a bias of H3K9me2 nucleation towards regions with low rates of C->T deamination, which typically lack DNA methylation. Lastly we examined the interaction of H3K9me2 and DNA methylation and determined that chromatin accessibility changes upon loss of H3K9me2 are dependent on the presence of DNA methylation. Examination of chromatin remodeling with FAIRE-seq in HSPCs treated with either a small molecule inhibitor of G9a/GLP or DMSO

2014-09-25 | E-GEOD-59749 | biostudies-arrayexpress

H3K9 dimethylation safeguards cancer cells against activation of the Interferon pathway [RNA-seq]

Project description:Activation of the interferon genes constitutes an important anticancer pathway, able to restrict proliferation of cancer cells. Here we demonstrate that the H3K9me3 histone methyl transferase (HMT) Suppressor Of Variegation 3-9 Homolog 1 (SUV39H1) is required for the proliferation of Acute Myeloid Leukemia (AML) and find that its loss leads to activation of the interferon pathway. Mechanistically, we show that this occur via destabilization of a complex composed of SUV39H1 and the two H3K9me2 HMTs G9a and GLP. Indeed, loss of H3K9me2 correlated with the activation of key interferon pathway genes and interference with the activities of G9a/GLP largely phenocopied loss of SUV39H1. Finally, we demonstrated that inhibition of G9a/GLP synergized with DNA demethylating agents and that SUV39H1 constitutes a potential biomarker the response to hypomethylation treatment. Collectively, we uncovered a clinical relevant role for H3K9me2 in safeguarding cancer cells against activation of the interferon pathway.

2022-03-18 | GSE160531 | GEO

H3K9 dimethylation safeguards cancer cells against activation of the Interferon pathway [ChIP-seq]

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