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CBFβ-SMMHC affects genome-wide Polycomb Repressive Complex 1 activity in Acute Myeloid Leukemia

ABSTRACT: CBFβ-SMMHC affects genome-wide Polycomb Repressive Complex 1 activity in Acute Myeloid Leukemia

PROVIDER: PRJNA528866 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15680484_1.fastq.gz	Fastqsanger.gz
	SRR15680484_2.fastq.gz	Fastqsanger.gz
	SRR15680485_1.fastq.gz	Fastqsanger.gz
	SRR15680485_2.fastq.gz	Fastqsanger.gz
	SRR8777090_1.fastq.gz	Fastqsanger.gz

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CBFβ-SMMHC affects genome-wide Polycomb Repressive Complex 1 activity in Acute Myeloid Leukemia

Project description:Polycomb activity is frequently altered in acute leukaemia through mutation or deletion of Polycomb Repressive Complex (PRC) components. Alterations in PRC-interacting factors such as the Core Binding Factor (CBF) complex should also affect leukemia biology, even if PRC composition is normal. We report that the acute myeloid leukemia (AML)-associated CBFβ-SMMHC fusion oncoprotein physically interacts with the PRC1 complex, and that these factors co-localize across the AML genome in a PRC2-independent manner. Depletion of CBFβ-SMMHC caused increases in genome-wide PRC1 binding and an altered association between PRC1 and RUNX1. Overall, PRC1 was more likely to be associated with active genes. CBFβ-SMMHC depletion had variable transcriptional effects, including significant reductions in expression of PRC1-bound ribosomal loci. Our results expand on the recently reported localized effect of CBFβ-SMMHC on RUNX1-mediated recruitment of PRC1 at MYC enhancer elements, providing evidence that the oncoprotein diversely affects Polycomb recruitment and transcriptional regulation across the entire AML genome.

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RUNX1 and CBFβ-SMMHC transactivate target genes together in abnormal myeloid progenitors for leukemogenesis

Project description:Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia (AML M4Eo), which generates a CBFB-MYH11 fusion gene. It is generally considered that CBFβ-SMMHC, the fusion protein encoded by CBFB-MYH11, is a dominant negative repressor of RUNX1. However, recent findings challenge the RUNX1-repression model for CBFβ-SMMHC mediated leukemogenesis. To definitively address the role of Runx1 in CBFB-MYH11 induced leukemia, we crossed conditional Runx1 knockout mice (Runx1f/f) with conditional Cbfb-MYH11 knockin mice (Cbfb+/56M). Upon Mx1-Cre activation in hematopoietic cells induced by poly (I:C) injection, all Mx1-CreCbfb+/56M mice developed leukemia in 5 months while no leukemia developed in Runx1f/fMx1-CreCbfb+/56M mice, and this effect was cell autonomous. Importantly, the abnormal myeloid progenitors (AMPs), a leukemia initiating cell population induced by Cbfb-MYH11 in the bone marrow, decreased and disappeared in Runx1f/fMx1-CreCbfb+/56M mice. RNA-seq analysis of AMP cells showed that genes associated with proliferation, differentiation blockage and leukemia initiation, were differentially expressed between Mx1-CreCbfb+/56M and Runx1f/fMx1-CreCbfb+/56M mice. In addition, with chromatin immunocleavage sequencing (ChIC-seq) assay, we observed a significant enrichment of RUNX1/CBFβ-SMMHC target genes in Runx1f/fMx1-CreCbfb+/56M cells, especially among down-regulated genes, suggesting that RUNX1 and CBFβ-SMMHC mainly function together as activators of gene expression through direct target gene binding. These data indicate that Runx1 is indispensable for Cbfb-MYH11 induced leukemogenesis by working together with CBFβ-SMMHC to regulate critical genes associated with the generation of a functional AMP population.

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The C-terminal multimerization domain is essential for leukemia development by CBFβ-SMMHC

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Loss of Cohesin regulator PDS5A reveals repressive role of Polycomb loops

Project description:Polycomb Repressive Complexes 1 and 2 (PRC1, PRC2) are conserved epigenetic regulators that promote transcriptional silencing. PRC1 and PRC2 converge on shared targets, catalyzing repressive histone modifications. In addition, a subset of PRC1/PRC2 targets engage in long-range interactions whose functions in gene silencing are poorly understood. Using a CRISPR screen in mouse embryonic stem cells, we discovered that the cohesin regulator PDS5A links transcriptional silencing by Polycomb and 3D genome organization. PDS5A deletion impairs cohesin unloading and results in derepression of subset of endogenous PRC1/PRC2 target genes. Importantly, derepression is not associated with loss of repressive Polycomb chromatin modifications. Instead, loss of PDS5A leads to aberrant cohesin activity, ectopic insulation sites and specific reduction of ultra-long Polycomb loops. We infer that these loops are important for robust silencing at a subset of Polycomb target genes and that maintenance of cohesin-dependent genome architecture is critical for Polycomb regulation.

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