ASH2L Regulates Postnatal Neurogenesis through Onecut2-mediated Inhibition of TGF-β Signaling Pathway
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE234685 | GEO | 2023/06/20
REPOSITORIES: GEO
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Project description:The ability of neural stem/progenitor cells (NSPCs) to proliferate and differentiate is required through different stages of neurogenesis. Disturbance in the regulation of neurogenesis causes many neurological diseases, such as intellectual disability, autism, and schizophrenia. However, the intrinsic mechanisms of this regulation in neurogenesis remain poorly understood. Here, we report that Ash2l (Absent, small or homeotic discs-like 2), one core component of a multimeric histone methyltransferase complex, is essential for NSPC fate determination during postnatal neurogenesis. Deletion of Ash2l in NSPCs impairs their capacity for proliferation and differentiation, leading to simplified dendritic arbors in adult-born hippocampal neurons and deficits in cognitive abilities. RNA sequencing data reveal that Ash2l primarily regulates cell fate specification and neuron commitment. Furthermore, we identified Onecut2, a major downstream target of ASH2L characterized by bivalent histone modifications, and demonstrated that constitutive expression of Onecut2 restores defective proliferation and differentiation of NSPCs in adult Ash2l-deficient mice. Importantly, we identified that Onecut2 modulates TGF-β signaling in NSPCs and that treatment with a TGF-β inhibitor rectifies the phenotype of Ash2l-deficient NSPCs. Collectively, our findings reveal the ASH2L-Onecut2-TGF-β signaling axis that mediates postnatal neurogenesis to maintain proper forebrain function.
| S-EPMC10406892 | biostudies-literature
Project description:ASH2L Regulates Postnatal Neurogenesis through Onecut2-mediated Inhibition of TGF-β Signaling Pathway
| PRJNA982756 | ENA
Project description:We showed a novel mechanism in which Ash2l directly binds to super-enhancers of several stemness genes to regulate pluripotency and self-renewal in pluripotent stem cells. Ash2l recruits Oct4/Sox2/Nanog (OSN) to form Ash2l/OSN complex at the super-enhancers of Jarid2, Nanog, Sox2, and Oct4, and further drives enhancer activation, upregulation of stemness genes, and maintains the pluripotent circuitry. Ash2l knockdown abrogates the OSN recruitment to all super-enhancers and further hinders the enhancer activation.
2020-01-24 | GSE136870 | 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 (Ash2l 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 Ash2l, 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.
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Project description:Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain tumor. Despite recent developments in surgery, chemo- and radiotherapy, a currently poor prognosis of GBM patients highlights an urgent need for novel treatment strategies. Our awareness on importance of epigenetic mechanisms for tumor initiation, progression and apoptotic response lead us to investigate epigenetic regulators of GBM survival through a genetic ablation screen. Screen with our custom library EPIDOKOL targeting functional domains of critical chromatin modifier genes, revealed multiple GBM essentiality gene candidates, most importantly ASH2L. Upon ASH2L ablation, we observed induction of apoptosis and cell cycle arrest concomitant with a set of downregulated signature genes. Massive reduction in tumor forming capacity of ASH2L depleted GBM cells as well as high ASH2L expression in GBM patients in comparison to low grade gliomas (LGG) proved essentiality of the gene for glioma cell fitness. Detection of epigenetic factors modulating tumor survival via high throughput, robust and affordable screens such as EPIDOKOL holds great promise to ultimately enable rapid discovery of novel cancer biomarkers and production of effective therapies which will increase life span and dignity of cancer patients.
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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.
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Project description:The Ash2l protein is a member of KMT2 enzyme complexes, which catalyse the (tri-)methylation of lysine 4 of Histone H3. H3K4me3 is considered a marker of actively transcribed genes. We determined changes in gene expression as a consequence of a conditional loss of Ash2l in the bone marrow. The expression data from the bone marrows of mice with floxed Ash2l exon 4 alleles without (control) or with an Mx1-Cre transgene (KO) and treated with synthetic dsRNA to induce recombination and the loss of Ash2l protein expression were compared.
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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:Glioblastoma is the most common and aggressive primary brain tumor with dismal prognosis, highlighting an urgent need for novel treatment strategies. In this study, we investigated epigenetic regulators of glioblastoma cell survival through CRISPR/Cas9 based genetic ablation screens using our customized sgRNA library EpiDoKOL, which targets critical functional domains of chromatin modifiers. Screens conducted in multiple cell lines revealed ASH2L, a histone lysine methyltransferase complex subunit, as a major regulator of glioblastoma cell viability. ASH2L depletion led to cell cycle arrest and apoptosis. RNA sequencing and Cut&Run sequencing together identified a set of cell cycle regulatory genes, such as TRA2B, BARD1, KIF20B, ARID4A, SMARCC1 that were downregulated upon ASH2L depletion. Mass spectrometry analysis demonstrated the interaction partners of ASH2L in glioblastoma cell lines as COMPASS family members including SETD1A, SETD1B, MLL1 and MLL2, however glioblastoma cells had differential dependency to COMPASS members for survival. The growth of ASH2L-depleted glioblastoma cells was markedly slower than controls in orthotopic in vivo models. TCGA analysis showed high ASH2L expression in glioblastoma compared to low grade gliomas and immunohistochemical analysis revealed significant ASH2L expression in glioblastoma tissues, attesting to its clinical relevance. Therefore, high throughput, robust and affordable screens with focused libraries, such as EpiDoKOL, holds great promise to enable rapid discovery of novel epigenetic regulators of cancer cell survival, such as ASH2L. Together, we suggest that targeting ASH2L could serve as a new therapeutic opportunity for glioblastoma.
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