Genome-wide distribution of Ash2L and H3K4me3 in mouse embryonic stem cell line E14
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE146933 | GEO | 2021/03/23
REPOSITORIES: GEO
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Project description:Genome-wide distribution of Ash2L and H3K4me3 in mouse embryonic stem cell line E14
| PRJNA612467 | ENA
Project description:Amplification of the 8p11-p12 genomic region occurs in 30% of luminal B breast cancers and results in coordinate overexpression of several oncogenes, including ASH2L, which upregulates gene expression via promoter tri-methylation of lysine 4 on histone 3 (H3K4me3). Since 8p11-p12 amplification is associated with endocrine resistance, the major cause of breast cancer mortality, understanding the underlying biology is essential to improving treatment options for patients. To explore the role of amplified and overexpressed ASH2L on epigenetic regulation of gene expression, we performed H3K4me3 ChIP-seq and RNA-seq in breast cancer cells with ASH2L amplification and overexpression following ASH2L knockdown and assessed the biological effects of the suite of genes identified in this manner. We discovered that ASH2L-regulated genes are implicated in cell cycle processes and response to the CDK4/6 inhibitor palbociclib and confirmed these effects in additional breast cancer cell lines. We also discovered that ASH2L regulates expression of another 8p11-p12 amplicon oncogene NSD3, also an epigenome modifier, which has previously been shown to result in overexpression and estrogen-independent activation of ERα. Together, these data establish ASH2L as a breast cancer oncogene and an important component of the 8p11-p12 amplicon that acts as an oncogenic unit in breast cancer.
2024-05-24 | GSE99669 | GEO
Project description:Cell fate decisions are closely associated with changes in gene expression programs. A large number of post-translational modifications of core histones contribute to controlling the expression of genes. A modification that is closely correlated with open chromatin and gene transcription is methylation of lysine 4 of histone H3 (H3K4). It is catalyzed by methyltransferases of the KMT2 family, which require interaction with 4 core subunits, WDR5, RBBP5, ASH2L and DPY30, for catalytic activity. Ash2l is required for organismal development and for tissue homeostasis in the mouse. In mouse embryo fibroblasts (MEFs), the loss of Ash2l results in downregulated gene expression, which provokes a senescence phenotype. We now find that both H3K4 mono- and tri-methylation (H3K4me1 and me3, respectively) are deregulated. H3K4me3 is lost while H3K4me1 is increased at promoters upon knockout of Ash2l. In particular, loss of H3K4me3 at promoters correlates with downregulation of gene expression, which is particularly obvious at CpG island promoters. Ash2l loss results in an increase of histone H3 loading at promoters, paralleled by enhanced chromatin compaction. This is accompanied by an increase of repressing and a decrease of activating histone marks. One of the sequence-specific transcription factors with altered binding upon depletion of Ash2l is CTCF. It is lost from some promoter-associated sites, but gained binding in other regions of the genome. This suggests that in addition to the well-known effects on H3K4 methylation upon depleting KMT2 complex components, Ash2l loss affects chromatin compaction. Whether the decrease of H3K4me3 promotes chromatin compaction at promoters or whether these are independent consequences of Ash2l loss remains to be determined. We suggest that both contribute mechanistically to gene repression and thus to the observed cellular effects.
2022-12-13 | GSE205230 | GEO
Project description:Cell fate decisions are closely associated with changes in gene expression programs. A large number of post-translational modifications of core histones contribute to controlling the expression of genes. A modification that is closely correlated with open chromatin and gene transcription is methylation of lysine 4 of histone H3 (H3K4). It is catalyzed by methyltransferases of the KMT2 family, which require interaction with 4 core subunits, WDR5, RBBP5, ASH2L and DPY30, for catalytic activity. Ash2l is required for organismal development and for tissue homeostasis in the mouse. In mouse embryo fibroblasts (MEFs), the loss of Ash2l results in downregulated gene expression, which provokes a senescence phenotype. We now find that both H3K4 mono- and tri-methylation (H3K4me1 and me3, respectively) are deregulated. H3K4me3 is lost while H3K4me1 is increased at promoters upon knockout of Ash2l. In particular, loss of H3K4me3 at promoters correlates with downregulation of gene expression, which is particularly obvious at CpG island promoters. Ash2l loss results in an increase of histone H3 loading at promoters, paralleled by enhanced chromatin compaction. This is accompanied by an increase of repressing and a decrease of activating histone marks. One of the sequence-specific transcription factors with altered binding upon depletion of Ash2l is CTCF. It is lost from some promoter-associated sites, but gained binding in other regions of the genome. This suggests that in addition to the well-known effects on H3K4 methylation upon depleting KMT2 complex components, Ash2l loss affects chromatin compaction. Whether the decrease of H3K4me3 promotes chromatin compaction at promoters or whether these are independent consequences of Ash2l loss remains to be determined. We suggest that both contribute mechanistically to gene repression and thus to the observed cellular effects.
2022-12-13 | GSE205231 | GEO
Project description:Cell fate decisions are closely associated with changes in gene expression programs. A large number of post-translational modifications of core histones contribute to controlling the expression of genes. A modification that is closely correlated with open chromatin and gene transcription is methylation of lysine 4 of histone H3 (H3K4). It is catalyzed by methyltransferases of the KMT2 family, which require interaction with 4 core subunits, WDR5, RBBP5, ASH2L and DPY30, for catalytic activity. Ash2l is required for organismal development and for tissue homeostasis in the mouse. In mouse embryo fibroblasts (MEFs), the loss of Ash2l results in downregulated gene expression, which provokes a senescence phenotype. We now find that both H3K4 mono- and tri-methylation (H3K4me1 and me3, respectively) are deregulated. H3K4me3 is lost while H3K4me1 is increased at promoters upon knockout of Ash2l. In particular, loss of H3K4me3 at promoters correlates with downregulation of gene expression, which is particularly obvious at CpG island promoters. Ash2l loss results in an increase of histone H3 loading at promoters, paralleled by enhanced chromatin compaction. This is accompanied by an increase of repressing and a decrease of activating histone marks. One of the sequence-specific transcription factors with altered binding upon depletion of Ash2l is CTCF. It is lost from some promoter-associated sites, but gained binding in other regions of the genome. This suggests that in addition to the well-known effects on H3K4 methylation upon depleting KMT2 complex components, Ash2l loss affects chromatin compaction. Whether the decrease of H3K4me3 promotes chromatin compaction at promoters or whether these are independent consequences of Ash2l loss remains to be determined. We suggest that both contribute mechanistically to gene repression and thus to the observed cellular effects.
2022-12-13 | GSE205232 | GEO
Project description:Epigenetic modulators are being recognized as attractive targets for potential cancer treatment. SET1/MLL complexes are the major H3K4 methyltransferase complexes in mammals. The DPY30 subunit is associated with these complexes by forming a dimer that directly binds to the ASH2L subunit in the complexes and facilitates methylation. We have previously established an important role of DPY30 in certain hematologic malignancies including MLL-rearranged leukemia and Burkitt’s lymphoma, but the domain on DPY30 that regulates cancer growth is not evident. Moreover, the potential of pharmacologically targeting this chromatin modulator to inhibit cancer has not been explored. Here we have developed a peptide-based strategy to specifically target DPY30 activity. We have designed cell-penetrating peptides that can either bind to DPY30 or show defective or enhanced binding to DPY30. The DPY30-binding peptides, but not the non-binding peptide, inhibit DPY30’s activity in interacting with ASH2L and in enhancing H3K4 methylation. Treatment with the DPY30-binding, but not the non-binding, peptide significantly inhibited the growth of MLL-rearranged leukemia and other MYC-dependent hematologic cancer cells including Burkitt’s lymphoma cells. These results strongly support a critical role of the ASH2L-binding groove of DPY30 in promoting the growth of certain blood cancers, and also demonstrate a proof-of-principle for the feasibility of pharmacologically targeting the ASH2L-binding groove of DPY30 for potential cancer inhibition.
2019-03-01 | GSE115988 | GEO
Project description:Post-translational modifications of core histones participate in controlling the expression of genes. Methylation of lysine 4 of histone H3 (H3K4) is associated with open chromatin and gene transcription. This histone mark is catalyzed by type 2 lysine methyltransferase (KMT2) complexes. In mammals, these consist of one of 6 different KMT2 enzymes, each associated with 4 core subunits, WDR5, RBBP5, ASH2L and DPY30, which are necessary for catalytic activity. The knockout of Ash2l is embryonically lethal in mice as well as in adult animals when hepatocytes or hematopoietic cells are targeted. To expand on the mechanistic understanding of Ash2l, we have used mouse embryo fibroblasts (MEFs). The knockout of Ash2l resulted in the downregulation of H3K4me3 at a large number of promoters, preferentially those associated with CpG islands, accompanied with broad repression of gene expression. The consequence in MEFs was induction of senescence concomitant with a set of down-regulated signature genes. Thus, although the loss of Ash2l in MEFs has broad and complex consequences on the transcriptional program, the biological consequences were distinct, culminating in senescence.
2024-08-14 | GSE165460 | GEO
Project description:Post-translational modifications of core histones participate in controlling the expression of genes. Methylation of lysine 4 of histone H3 (H3K4) is associated with open chromatin and gene transcription. This histone mark is catalyzed by type 2 lysine methyltransferase (KMT2) complexes. In mammals, these consist of one of 6 different KMT2 enzymes, each associated with 4 core subunits, WDR5, RBBP5, ASH2L and DPY30, which are necessary for catalytic activity. The knockout of Ash2l is embryonically lethal in mice as well as in adult animals when hepatocytes or hematopoietic cells are targeted. To expand on the mechanistic understanding of Ash2l, we have used mouse embryo fibroblasts (MEFs). The knockout of Ash2l resulted in the downregulation of H3K4me3 at a large number of promoters, preferentially those associated with CpG islands, accompanied with broad repression of gene expression. The consequence in MEFs was induction of senescence concomitant with a set of down-regulated signature genes. Thus, although the loss of Ash2l in MEFs has broad and complex consequences on the transcriptional program, the biological consequences were distinct, culminating in senescence.
2022-08-12 | GSE165458 | GEO
Project description:The trithorax protein ASH2L is essential for organismal and tissue development and for cell proliferation. ASH2L is a subunit of KMT2/COMPASS methyltransferase complexes that catalyze the methylation of histone H3 lysine 4 (H3K4). Tri- and mono-methylation of H3K4 (H3K4me3 and H3K4me1) are associated with active promoters and enhancers, respectively. The molecular relevance of these modifications is not fully understood. We have used mouse embryo cells with a PROTAC-sensitive, degradable ASH2L to assess the functional consequences of KMT2 complex inactivation. The rapid loss of ASH2L resulted in a sequential alterations of histone marks at promoters, first a decrease of H3K4me3, then an increase of H3K4me1, and a decrease of H3K27ac during the first 16 hrs, while an increase in H3K27me3 was very slow. These consequences were most prominent at CpG island promoters within a window of ±1 kb of the transcription start sites. Despite the the rapid loss of ASH2L, the effect on transcription in the first 8 hrs was minimal. This was accompanied with an alterations in gene expression and associated proliferation stop and cell cycle arrest. These findings suggest an order series of events upon loss of ASH2L that requires considerable amount of time to unfold.
2023-09-12 | GSE240994 | GEO
Project description:Meiosis is precisely controlled by complex gene expression programs and involves epigenetic reprogramming and silencing of transposable elements. ASH2L (Absent, small or homeotic 2-like) is a core component of KMT2 complexes conferring H3K4 trimethylation, and plays key roles in mouse embryonic development, neurogenesis, and liver function. However, its role in meiosis remains elusive. Here, we demonstrate an essential role of Ash2l for meiosis. Using a germ cell-specific Ash2l knockout mouse model, we found that Ash2l deficiency leads to meiotic arrest and sterility in both sexes. Ash2l-deficient spermatocytes exhibit failures in chromosomal synapsis, blockades in meiotic recombination, and increased apoptosis. Mechanistically, we found that the Ash2l deficiency results in a global loss of H3K4me3 in promoter regions and significantly decreases expression of thousands of genes, including those for H3K9 di-methylation, DNA methylation and transposon repression, crucial for meiotic prophase I progression. Furthermore, we observed that Ash2l mutant spermatocytes display hypomethylation at transposon sites and ectopic expression of LINE1-ORF1P. Our findings thus reveal a previously unappreciated role of the ASH2L-dependent H3K4me3 modification and provide clues to the molecular mechanisms in epigenetic disorders underlying male infertility.
2024-10-19 | GSE246296 | GEO