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Sci Adv. 2017 Jan 20;3(1):e1601602. doi: 10.1126/sciadv.1601602. eCollection 2017 Jan.

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

Author information

1
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
2
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
3
Department of Electrical and Computer Engineering and TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, College Station, TX 77843, USA.
4
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
5
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA.
6
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.; Department of Internal Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
7
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.; Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

Abstract

ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 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 Asxl1 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 Asxl1 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.

KEYWORDS:

ASXL1; cohesin complex; gene regulation; hematopoiesis

PMID:
28116354
PMCID:
PMC5249256
DOI:
10.1126/sciadv.1601602
[Indexed for MEDLINE]
Free PMC Article

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