ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis

Abstract

<i>ASXL1</i> is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of <i>Asxl1</i> leads to myelodysplastic syndrome-like disease in mice; however, the underlying molecular mechanisms remain unclear. We report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromatid segregation and regulate gene expression. Loss of <i>Asxl1</i> impairs the cohesin function, as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. Chromatin immunoprecipitation followed by DNA sequencing data revealed that ASXL1, RAD21, and SMC1A share 93% of genomic binding sites at promoter regions in Lin^-cKit⁺ (LK) cells. We have shown that loss of <i>Asxl1</i> reduces the genome binding of RAD21 and SMC1A and alters the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and regulate gene expression in hematopoietic cells.