Publication Date:
2015-12-03
Description:
Recurrent somatic loss-of-function mutations in ASXL1 (Addition of sex combs-like 1) are common genetic events in a spectrum of myeloid malignancies and these alterations demarcate patients with poor outcome. ASXL1 forms a chromatin regulatory complex with the ubiquitin hydrolase BAP1 (BRCA1 associated protein-1), a protein that has been found to be transcriptionally repressed in MDS patients. These data are consistent with BAP1 having tumor suppressive activity in MDS; however, the mechanism by which disruption of the ASXL1-BAP1 axis leads to transformation is not well understood. We conditionally deleted Bap1 in the murine hematopoietic system utilizing Mx1-Cre (hereafter referred to as Bap1 KO). One hundred percent of mice with confirmed Bap1 deletion developed a fully penetrant MDS-like disease characterized by leukocytosis, anemia, and splenomegaly. Bap1 KO mice have an expansion of the granulocyte macrophage progenitor compartment (GMP; Lin- c-Kit+ Sca1- CD34+ Fcϒ+). Given the role of BAP1 in epigenetic regulation, we investigated the effect of Bap1 loss on chromatin state and transcriptional output. We first assessed epigenetic changes in Bap1 KO mice by performing histone mass spectometry in control and Bap1 KO hematopoietic stem and progenitor cells (HSPCs, c-Kit+ enriched). Bap1 loss increased H3K27me2/3 at the expense of H3K27me0/1. We confirmed that H3K27me3 was increased in Bap1 KO bone marrow cells by completing H3K27me3 ChIP-Sequencing in HSPCs. Enumeration of H3K27me3 peaks in Bap1 KO versus control cells indicated an increase in H3K27me3 domains (Figure A). We next overlaid RNA-Sequencing from GMP sorted Bap1 KO bone marrow cells with genes marked by H3K27me3, as indicated by ChIP-Sequencing. We found that Bap1 loss resulted in a global decrease in gene expression (68% downregulated, 657/968 genes, p-adj
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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