Neuronal Ash1L Gates Skin Psoriasis Via Activity-dependent Release of miR-let-7b
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE215333 | GEO | 2024/10/31
REPOSITORIES: GEO
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Project description:The histone methyltransferases MLL and ASH1L are trithorax-group proteins that interact genetically through undefined molecular mechanisms to regulate developmental and hematopoietic gene expression. Here we show that the lysine 36-dimethyl mark of histone H3 (H3K36me2) written by ASH1L is preferentially bound in vivo by LEDGF, an MLL-associated protein that co-localizes with MLL, ASH1L and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild type MLL proteins to chromatin at key leukemia target genes, and is a crucial regulator of MLL-dependent transcription and leukemic transformation. Conversely KDM2A, an H3K36me2 demethylase and Polycomb-group silencing protein, antagonizes MLL-associated leukemogenesis. Our studies illuminate the molecular mechanisms underlying epigenetic interactions wherein placement, interpretation and removal of H3K36me2 contribute to the regulation of gene expression and MLL leukemia, and suggest ASH1L as a target for therapeutic intervention. Investigation of multiple transcription factors and histone modification marks in MV4-11 human leukemia cells.
2016-07-01 | E-GEOD-73528 | biostudies-arrayexpress
Project description:ASH1L and MLL1 are two histone methyltransferases that facilitate transcriptional activation during normal development. However, the roles of ASH1L and its enzymatic activity in the development of MLL-rearranged leukemias are not fully elucidated in Ash1L gene knockout animal models. In this study, we used an Ash1L conditional knockout mouse model to show that loss of ASH1L in hematopoietic progenitor cells impaired the initiation of MLL-AF9-induced leukemic transformation in vitro. Furthermore, genetic deletion of ASH1L in the MLL-AF9-transformed cells impaired the maintenance of leukemic cells in vitro and largely blocked the leukemia progression in vivo. Importantly, the loss of ASH1L function in the Ash1L-deleted cells could be rescued by wild-type but not the catalytic-dead mutant ASH1L, suggesting the enzymatic activity of ASH1L was required for its function in promoting MLL-AF9-induced leukemic transformation. At the molecular level, ASH1L enhanced the MLL-AF9 target gene expression by directly binding to the gene promoters and modifying the local histone H3K36me2 levels. Thus, our study revealed the critical functions of ASH1L in promoting the MLL-AF9-induced leukemogenesis, which provides a molecular basis for targeting ASH1L and its enzymatic activity to treat MLL-arranged leukemias.
2021-09-07 | GSE183413 | GEO
Project description:To recognize DNA damage, nucleotide excision repair (NER) deploys a multipart mechanism by which the XPC sensor detects helical distortions followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place on chromatin where DNA is wrapped around histones. We show that the histone methyltransferase ASH1L, once activated by MRG15, accelerates global-genome NER activity. Upon UV irradiation, ASH1L deposits H3K4me3 marks all over the genome (except in gene promoters), thus priming chromatin for relocations of XPC from native to damaged DNA. ASH1L further recruits the histone chaperone FACT to UV lesions. In the absence of ASH1L, MRG15 or FACT, XPC persists on damaged DNA without being able to deliver lesions to the TFIIH verifier. We conclude that ASH1L implements repair hotspots whose H3K4me3 and FACT occupancy confers an active promoter-like code and organization of histones that make DNA damage verifiable by the NER machinery.
2023-06-08 | GSE227008 | GEO
Project description:The histone methyltransferase ASH1L, first discovered for its role in transcription, has been shown to accelerate the removal of ultraviolet (UV) light-induced cyclobutane pyrimidine dimers (CPDs) by nucleotide excision repair. Previous reports demonstrated that CPD excision is most efficient at transcriptional regulatory elements, including enhancers, relative to other genomic sites. Therefore, we analyzed DNA damage maps in ASH1L-proficient and ASH1L-deficient cells to understand how ASH1L controls enhancer stability. This comparison showed that ASH1L protects enhancer sequences against the induction of CPDs besides stimulating repair activity. ASH1L reduces CPD formation at C-containing but not at TT dinucleotides, and no protection occurs against pyrimidine-(6,4)-pyrimidone photoproducts or cisplatin crosslinks. The diminished CPD induction extends to gene promoters but excludes retrotransposons. This guardian role against CPDs in regulatory elements is associated with the presence of H3K4me3 and H3K27ac histone marks, which are known to interact with the PHD and BRD motifs of ASH1L, respectively. Molecular dynamics simulations identified a DNA-binding AT hook of ASH1L that alters the distance and dihedral angle between neighboring C nucleotides to disfavor dimerization. The loss of this protection results in a higher frequency of C–>T transitions at enhancers of skin cancers carrying ASH1L mutations compared to ASH1L-intact counterparts.
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Project description:The histone methyltransferase ASH1L, first discovered for its role in transcription, has been shown to accelerate the removal of ultraviolet (UV) light-induced cyclobutane pyrimidine dimers (CPDs) by nucleotide excision repair. Previous reports demonstrated that CPD excision is most efficient at transcriptional regulatory elements, including enhancers, relative to other genomic sites. Therefore, we analyzed DNA damage maps in ASH1L-proficient and ASH1L-deficient cells to understand how ASH1L controls enhancer stability. This comparison showed that ASH1L protects enhancer sequences against the induction of CPDs besides stimulating repair activity. ASH1L reduces CPD formation at C-containing but not at TT dinucleotides, and no protection occurs against pyrimidine-(6,4)-pyrimidone photoproducts or cisplatin crosslinks. The diminished CPD induction extends to gene promoters but excludes retrotransposons. This guardian role against CPDs in regulatory elements is associated with the presence of H3K4me3 and H3K27ac histone marks, which are known to interact with the PHD and BRD motifs of ASH1L, respectively. Molecular dynamics simulations identified a DNA-binding AT hook of ASH1L that alters the distance and dihedral angle between neighboring C nucleotides to disfavor dimerization. The loss of this protection results in a higher frequency of C–>T transitions at enhancers of skin cancers carrying ASH1L mutations compared to ASH1L-intact counterparts.
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Project description:The ASH1L lysine methyltransferase plays a critical role in development and is frequently dysregulated in cancer and neurodevelopmental diseases. ASH1L catalyzes mono- and dimethylation of histone H3K36 and contains a set of uncharacterized domains. Here, we report the structure-function relationships of the C-terminal cassette of ASH1L encompassing a bromodomain (BD), a PHD finger and a bromo-associated homology (BAH) domain and show that ASH1L co-localizes with H3K4me3 but not with H3K36me2 at transcription start sites genome-wide and is involved in embryonic stem cell differentiation and transcriptional regulation of differentiation marker genes. Our crystal and NMR structural data provide mechanistic details for the recognition of H3K4me3 by PHD, the DNA binding activities of BD and BAH, and crosstalk among these domains. We show that the PHD-H3K4me3 interaction is inhibitory to the catalytic activity of ASH1L and that the DNA binding function of BAH is necessary for ASH1L engagement with the nucleosome. Our findings suggest a mechanism by which the C-terminus of ASH1L associates with chromatin and provide molecular and structural insights that are essential in therapeutic targeting of ASH1L.
2023-04-23 | GSE199438 | GEO
Project description:The histone methyltransferases MLL and ASH1L are trithorax-group proteins that interact genetically through undefined molecular mechanisms to regulate developmental and hematopoietic gene expression. Here we show that the lysine 36-dimethyl mark of histone H3 (H3K36me2) written by ASH1L is preferentially bound in vivo by LEDGF, an MLL-associated protein that co-localizes with MLL, ASH1L and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild type MLL proteins to chromatin at key leukemia target genes, and is a crucial regulator of MLL-dependent transcription and leukemic transformation. Conversely KDM2A, an H3K36me2 demethylase and Polycomb-group silencing protein, antagonizes MLL-associated leukemogenesis. Our studies illuminate the molecular mechanisms underlying epigenetic interactions wherein placement, interpretation and removal of H3K36me2 contribute to the regulation of gene expression and MLL leukemia, and suggest ASH1L as a target for therapeutic intervention.
2016-07-01 | GSE73528 | GEO
Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remains undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes a new ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.
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Project description:The H3K36me2 and ASH1L levels are compared in the presence or absence of the inhibitor of the ASH1L activity.
2021-02-24 | GSE150086 | GEO
Project description:Myoblast fusion (MF) is a complex process required for muscle formation. During development, post-natal muscle growth and adult muscle regeneration, myoblasts proliferate and fuse to generate multinucleated fibers. MF defects have been described in an increasing number of muscle diseases. Moreover, MF plays also a relevant role in the delivery of therapeutics to muscle fibers. Hence, the identification of novel MF activators bears strong therapeutic relevance. Despite the central role of MF, the mechanisms governing this process are incompletely understood, and no epigenetic regulator has ever been described. Ash1L is a histone methyltransferase responsible for H3K36me2 and a member of the Trithorax group of epigenetic activators. It is involved in several diseases, including FSHD muscular dystrophy, autism and cancer. Nevertheless, its physiological role in skeletal muscle is unknown. For the first time, we found that Ash1L expression is regulated during skeletal muscle development, positively correlated with that of key MF genes and reduced in Duchenne muscular dystrophy. During physiological muscle differentiation or muscle regeneration, Ash1L shows a peak of expression coincident with the activation of MF. Loss-of-function experiments support a selective and evolutionary conserved requirement for Ash1L in MF. Accordingly, Ash1L KO mice display small and underdeveloped skeletal muscles due to a MF defect. By combining RNA- and ChIP-sequencing, we identified direct Ash1L targets in muscle. Intriguingly, nearly all of them are known Polycomb target genes suggesting that Ash1L is required to counteract Polycomb repressive activity to allow activation of key myogenesis genes. In particular, we found that Ash1L drives MF by directly activating the expression of the key MF gene Cdon. Our results promote Ash1L as the first epigenetic regulator of MF and suggest that its activity could be targeted to improve cell therapy for muscle diseases.
2018-10-02 | GSE110957 | GEO