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Recruitment of BRD4 to the ASXL1 genomic targets depends on the extra-terminal domain of BRD4

ABSTRACT: Additional sex combs like 1 (ASXL1) is a well-established driver of a wide range of cancers. Here, we identified a high level of genetic correlation between ASXL1 and the major transcriptional activator BRD4 in cancer cells and characterized the molecular mechanism underlying this correlation. Structural and biochemical data show the formation of a tight complex between the extraterminal domain of BRD4 (BRD4ET) and the ET-binding motif of ASXL1 (ASXL1EBM). ChIP-seq analysis of ASXL1 impaired in binding to BRD4ET demonstrates that the recruitment of BRD4 to the ASXL1 genomic targets is ASXL1EBM-dependent. We find that the cancer-related truncated variants comprising residues 1-645 and 1-591 of ASXL1 (ASXL11-645 and ASXL11-591) retain BRD4 binding function, with ASXL11-645 showing an enhanced ability to recruit BRD4 to promoters of ASXL1 target genes. Genomic data from six cancer types reveals a strong positive ASXL1-BRD4 relationship, with BRD4 occupying the ASXL1 promoter and thus further suggesting a possible feed-forward mechanism. Our findings shed light on the mechanistic details by which ASXL1 associates with BRD4 and may provide potential therapeutic avenues for developing cancer treatments through targeting the ASXL1-BRD4 axis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302969 | GEO | 2025/12/22

REPOSITORIES: GEO

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Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation

Project description:Additional Sex Combs Like 1 (ASXL1) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that ASXL1 mutations might confer an alteration of function. Here we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphologic dysplasia. Although expression of mutant Asxl1 altered the functions of hematopoietic stem cells (HSCs), it maintained their survival in competitive transplantation assays and increased susceptibility to leukemic transformation by co-occurring RUNX1 mutation or viral insertional mutagenesis. KI mice displayed substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3, distinct from the effects of Asxl1 loss. ChIP-seq analysis demonstrated opposing effects of wildtype and mutant Asxl1 on H3K4me3. These findings reveal that ASXL1 mutations confer HSCs with an altered epigenome and increase susceptibility for leukemic transformation, presenting a novel model for CHIP.

2018-02-28 | GSE111067 | GEO

Recruitment of BRD4 to the ASXL1 genomic targets depends on the extra-terminal domain of BRD4

Project description:Recruitment of BRD4 to the ASXL1 genomic targets depends on the extra-terminal domain of BRD4

| PRJNA1293178 | ENA

ASXL1 Directs Neutrophilic Differentiation via Modulation of MYC and RNA Polymerase II

Project description:Mutations in the gene Additional Sex-Combs Like 1 (ASXL1) are recurrent in myeloid malignancies as well as the pre-malignant condition clonal hematopoiesis, where they are universally associated with poor prognosis. An epigenetic regulator, ASXL1 canonically directs the deposition of H3K27me3 via the polycomb repressive complex 2. However, its precise role in myeloid lineage maturation is incompletely described. We utilized single cell RNA sequencing (scRNA-seq) on a murine model of hematopoietic-specific ASXL1 deletion and identified a specific role for ASXL1 in terminal granulocyte maturation. Terminal maturation is accompanied by down regulation of Myc expression and cell cycle exit. ASXL1 deletion leads to hyperactivation of Myc in granulocyte precursors and a quantitative decrease in neutrophil production. This failure of normal developmentally-associated Myc suppression is not accompanied by significant changes in the landscape of covalent histone modifications including H3K27me3. Examining the genome-wide localization of ASXL1 in myeloid progenitors revealed strong co-localization with RNA Polymerase II (RNAPII) at the promoters and spread across the gene bodies of transcriptionally active genes. ASXL1 deletion results in a decrease in RNAPII promoter-proximal pausing in granulocyte progenitors, indicative of a global increase in productive transcription, consistent with the known role of ASXL1 as a mediator of RNAPII pause release. These results suggest that ASXL1 inhibits productive transcription in granulocyte progenitors, identifying a new role for this epigenetic regulator and highlighting a novel possible oncogenic mechanism for ASXL1 mutations in myeloid malignancies.

2023-02-08 | GSE158184 | GEO

Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119

Project description:Mutations in additional sex combs like 1 (ASXL1) confer poor prognosis in myeloid malignancies and are also found in pre-malignant clonal hematopoiesis of indeterminate potential (CHIP). However, the mechanisms by which these mutations contribute to disease initiation remain unresolved and therapeutic targeting has remained elusive. Here, we demonstrate that ASXL1 mutations are frequently founding lesions in acute myeloid leukemia (AML) and lead to the expression of a functional, truncated protein. We developed a human disease model that faithfully recapitulates ASXL1-mutant CHIP with increased self-renewal and in vivo competitive advantage that can spontaneously progress to a lethal myeloid malignancy. We determined that truncated ASXL1 leads to global redistribution of the repressive chromatin mark H2AK119Ub, increased chromatin accessibility, and activation of both myeloid and stem cell gene expression programs. Finally, we identified dysregulation of H2AK119Ub as a therapeutic vulnerability and demonstrated that ASXL1-mutant cells are vulnerable to inhibition of the PRC1 complex.

2024-02-07 | GSE190738 | GEO

ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer

Project description:The bromodomain and extra-terminal (BET) protein BRD4 functions as a transcriptional activator and is a therapeutic target for different human cancers. Here, we report a critical link between Polycomb repressive deubiquitinase-BAP1 (PR-DUB) complex and BRD4, which is bridged by the physical interaction between additional sex combs-like protein 3 (ASXL3) in small cell lung cancer (SCLC). We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4-extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 at active enhancers. Genetic depletion of ASXL3 leads to a genome-wide reduction of histone H3K27Ac levels as well as BRD4 occupancy, resulting in a similar change of gene expression profile induced by BET inhibitors. Pharmacologically-induced inhibition with BET specific chemical degrader (dBET6) selectively inhibits cell proliferation of a subtype of SCLC, characterized with high expression of ASXL3. Collectively, this study provides mechanistic insight into the oncogenic function of ASXL3-BRD4 axis in SCLC.

2020-06-24 | GSE145028 | GEO

Asxl1 mutation enhances differentiation in CSF3R-mutated myeloproliferative neoplasms [Cut & Tag]

Project description:Mutations in the epigenetic regulator Additional Sex Combs-Like 1 (ASXL1) are frequently observed in chronic neutrophilic leukemia (CNL). This disease is classically driven by activating mutations in Colony Stimulating Factor 3 Receptor (CSF3R), which promote the overproduction of neutrophils that characterizes this disease. Despite high rates of co-occurrence, the interplay between ASXL1 and CSF3R mutations in hematopoiesis and leukemia development remains poorly understood. Here, we present a new mouse model with both Asxl1Y588X and Csf3rT621I mutations, which recapitulates features of human CNL. Csf3r-mutant mice exhibit an age-associated depletion of hematopoietic stem and progenitor cells, which is reversed by the addition of Asxl1Y588X. This combination of mutations causes an expansion of myeloid-biased stem cells. As the mice age they develop neutrophilia, but leukemia is rare, suggesting additional mutations may be required for transformation. Using models of myeloid differentiation, we find that ASXL1 truncation enhances CSF3RT618I-driven neutrophil differentiation by downregulating MYC programs and activating inflammatory pathways associated with mature myeloid cell production. Moreover, cells with both mutations had increased priming of neutrophil-associated enhancers and reduced priming of enhancers associated with monocytic differentiation. Mutant ASXL1 is known to decrease genome-wide abundance of a repressive histone mark—H2AK119ub. While we see the expected decrease in H2AK119ub in Asxl1-mutant cells, this effect is reversed when CSF3R is also mutated, suggesting a complex interplay between these mutations in regulating chromatin dynamics during hematopoiesis. Our findings highlight context-dependent effects of ASXL1 mutation in myeloid disorders and provide insights into the mechanisms underlying neutrophil differentiation in ASXL1-mutant CNL.

2025-01-22 | GSE266090 | GEO

Asxl1 mutation enhances differentiation in CSF3R-mutated myeloproliferative neoplasms [ATAC-Seq]

2025-01-22 | GSE266087 | GEO

Asxl1 mutation enhances differentiation in CSF3R-mutated myeloproliferative neoplasms [RNA-Seq]

2025-01-22 | GSE266091 | GEO

BRD4 binding sites in transformed fibroblasts

Project description:Analysis of BRD4 ChIP-seq data of two types of human transformed fibroblasts (WT and HGPS) to identify specific and common binding sites for BRD4. Transformed cell lines were obtained by retroviral introduction of TERT (T), V12-HRAS (R) and SV40 large and small T antigens (S) of primary skin fibroblasts for HGPS patients (TRS-HGPS) and age-matched control wild-type individuals (TRS-WT) Abstract: Advanced age and DNA damage accumulation are strong risk factors for cancer. The premature-aging disorder Hutchinson Gilford Progeria Syndrome (HGPS) provides a unique opportunity to study the interplay between DNA damage and aging-associated tumor mechanisms, since HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neo-plastic transformation. This resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells leading to inhibition of oncogenic de-differentiation. BRD4 also in-hibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals and BRD4-mediated tumor protection is clinically relevant, since a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific functions for BRD4 in tumorigenesis. Examination of BRD4 binding events in TRS-WT and TRS-HGPS fibroblasts (2 independent cell lines in each group)

2014-10-02 | E-GEOD-61325 | biostudies-arrayexpress

ASXL1/2 links MLL4 and BAP1 on enhancers

Project description:Histone H3K4 monomethyltransferases MLL3 and MLL4 contain a set of uncharacterized PHD fingers. By structural and biochemical assays, we found a novel function of the PHD2 and PHD3 (PHD2/3) fingers of MLL3 and MLL4, revealing their direct binding to the conserved MBH (MLL binding helix) region of ASXL1/2, components of the Polycomb repressive PR-DUB complex. In mouse embryonic stem cells, we observed that BAP1, the catalytic subunit of the PR-DUB complex, physically interacts with MLL4 in an ASXL1/2 MBH-dependent manner. Genomic studies demonstrate that the ASXL1/2 MBH is required for BAP1 binding on active enhancers and suggest that MLL4 facilitates BAP1 binding on active enhancers through ASXL1/2 MBH.

2024-04-30 | GSE248027 | GEO

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