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Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche

ABSTRACT: ASH1L promotes cancer metastasis, we performed single-cell RNA sequencing (scRNA-seq) to investigate the impact of ASH1L on the crosstalk of invading cancer cells and immune cells in metastatic bone niches

ORGANISM(S): Mus musculus

PROVIDER: GSE269895 | GEO | 2025/03/25

REPOSITORIES: GEO

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Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche (RNA-Seq)

Project description:Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we uncover that histone methyltransferase ASH1L is genetically amplified in metastatic diseases and is required for cancer invasiveness and bone metastasis. In invading cancer cells, ASH1L rewires methylations at H3K4 and H3K36 and cooperates with transcriptional factor HIF-1α to induce pro-metastatic transcriptome. Leveraging our newly developed metastasis models and single-cell transcriptomic profiling, we demonstrate that ASH1L in invading cancer cells induces monocyte differentiation into lipid-associated macrophage (LA-TAM) and maintains their pro-tumoral and anti-inflammatory phenotype in the metastatic bone niche. Mechanistic studies reveal that IGF-2 is a direct target of ASH1L and mediates LA-TAMs’ differentiation and phenotypic changes by reprogramming oxidative phosphorylation. In patients with metastatic cancers, ASH1L overexpression is associated with enriched LA-TAMs. As a proof of concept, pharmacologic inhibition of the ASH1L-macrophages axis elicits robust anti-metastasis responses in preclinical models.

2025-03-20 | GSE269830 | GEO

Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche (CUT&RUN)

2025-03-20 | GSE269829 | GEO

Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche

Project description:Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche

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Histone H3K36me2-specific methyltransferase ASH1L promotes the MLL-AF9-induced leukemogenesis

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

Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche (RNA-Seq)

Project description:Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche (RNA-Seq)

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Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche (CUT&RUN)

Project description:Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche (CUT&RUN)

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ASH1L methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair [ChIP-Seq ASH1L-CTD]

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

Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation

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

Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors

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.

2021-05-23 | GSE173262 | GEO

ASH1L methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair [ATAC-Seq]

2023-06-08 | GSE227007 | GEO