ASXL1/2 links MLL4 and BAP1 on enhancers
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1041429 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26856529_1.fastq.gz | Fastqsanger.gz | |||
| SRR26856529_2.fastq.gz | Fastqsanger.gz | |||
| SRR26856530_1.fastq.gz | Fastqsanger.gz | |||
| SRR26856530_2.fastq.gz | Fastqsanger.gz | |||
| SRR26856531_1.fastq.gz | Fastqsanger.gz |
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Project description:ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring-Opitz syndrome. Here, we demonstrate that truncated ASXL1 proteins confer enhanced activity on the ASXL1-BAP1 complex. Stable expression of truncated, hyperactive ASXL1-BAP1 complexes in a hematopoietic precursor cell line resulted in global erasure of H2AK119Ub, striking depletion of H3K27me3, selective upregulation of a subset of genes whose promoters bore both H2AK119Ub and H3K4me3, and spontaneous differentiation to the mast cell lineage. These outcomes required the catalytic activity of BAP1, indicating these events were downstream consequences of H2AK119Ub erasure. In bone marrow precursors, truncated ASXL1-BAP1 expression cooperated with TET2 loss-of-function to increase differentiation to the myeloid lineage in vivo. We propose that pathological ASXL1 mutations confer gain-of-function on the ASXL-BAP1 complex. ChIP-Seq for H2AK119Ub, H3K4me3, H3K27me3 on EML cells. RNA-Seq on EML cells expressing ASXL1(1-479)+BAP1 and control.
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Project description:Our genomic studies show that ~20% of MLL4 chromatin binding sites overlap with BAP1 binding regions in HCT116 human colon cancer cells. By comparing MLL4 and BAP1 localization in wild type and knockout cells, we show an interdependent genomic binding of MLL4 and BAP1 on MLL4+ BAP1+ enhancers. Profiling of transcriptomes reveals that a small subset of gene expression is co-regulated by MLL4 and BAP1. Together, our findings identify a functional interaction between enhancer H3K4 methyltransferase MLL4 and H2A deubiquitinase.
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Project description:Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for the deposition of H3K4me1/2 on enhancers remain elusive. Furthermore, the functions of these methyltransferases on enhancers and associated cell-type-specific gene expression are poorly understood. Here, we identify MLL4 (KMT2D) as a major H3K4 mono- and di-methyltransferase in mammalian cells. Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of MLL4 dramatically decreases H3K4me1/2 and H3K27ac on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Finally, we provide evidence that lineage-determining TFs recruit and require MLL4 to establish enhancers critical for cell-type-specific gene expression. Together, these results identify MLL4 as an H3K4 mono-/di-methyltransferase required for enhancer activation during cell differentiation. ChIP-Seq analyses of C/EBPbeta, MLL4 and histone modifications (H3K4me1, H3K27ac) in vec- or C/EBPbeta-overexpressing, adenoviral GFP- or Cre-infected, MLL3-/-MLL4-flox/flox brown preadipocytes without induction of differentiation.
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