The interdependency between MiDAC complex and MLL3/4 complexes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA786640 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17148900.fastq.gz | Fastqsanger.gz | |||
| SRR17148901.fastq.gz | Fastqsanger.gz | |||
| SRR17148902.fastq.gz | Fastqsanger.gz | |||
| SRR17148903.fastq.gz | Fastqsanger.gz | |||
| SRR17148904_1.fastq.gz | Fastqsanger.gz |
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Project description:Class-switch recombination (CSR) diversifies antibodies for productive immune responses while maintaining stability of the B cell genome. Transcription at the immunoglobulin heavy-chain (Igh) locus targets CSRassociated DNA damage and is promoted by the BRCT domain-containing PTIP protein. Although PTIP is a unique component of the MLL3/MLL4 chromatin-modifying complex, the mechanisms for how PTIP promotes transcription remain unclear. Here we dissect the minimal structural requirements of PTIP and its different protein complexes using quantitative proteomics in primary lymphocytes. We find that PTIP functions in transcription and CSR separately from its association with the MLL3/MLL4 complex and from its localization to sites of DNA damage. We identify a tandem BRCT domain of PTIP that is sufficient for CSR and identify PA1 as its main functional protein partner. Collectively, we provide genetic and biochemical evidence that a PTIP-PA1 subcomplex functions independently from the MLL3/MLL4 complex to mediate transcription during CSR. These results further our understanding of how multi-functional chromatin-modifying complexes are organized by subcomplexes that harbor unique and distinct activities.
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Project description:An imbalance in the activities of the Polycomb and Trithorax complexes underlies numerous human pathologies, including cancer. The BAP1 deubiquitinase (DUB) complex negatively regulates Polycomb activity and also recruits the Trithorax histone H3K4 methyltransferase, MLL3/COMPASS, to the enhancers of tumor suppressor genes. We and others have demonstrated that the BAP1-MLL3 pathway is mutated in several differ cancers. Yet, how BAP1 recruits MLL3 to these loci remains a fundamentally important unanswered question. Here we demonstrate that ASXL2 directly mediates the interaction between the BAP1 complex and MLL3/COMPASS. ASXL2 loss abolishes the MLL3-BAP1 interaction, leading to decreased MLL3 occupancy at enhancers and reduced expression of BAP1-MLL3 target genes. The interaction between ASXL2 and MLL3 is negatively regulated by protein arginine methyltransferase 4 (PRMT4, also known as CARM1), which methylates ASXL2 on R639/R641. Methylation of ASXL2 by CARM1 blocks binding to MLL3 binding and impairs the expression of MLL3 dependent genes. This finding uncovers a novel transcription repression function for CARM1 and provides a unique insight into the BAP1/ASXL2/MLL3 axis, which is controlled by arginine methylation and could serve as a target for potential cancer therapeutics.
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