Abstract：
:Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoietic stem cells and during the early development of acute myeloid leukemia and other myeloid malignancies. Although cohesins are involved in chromosome separation and DNA damage repair, cohesin complex functions during hematopoiesis and leukemic development are unclear. Here, we show that mutant cohesin proteins block differentiation of human hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo and enforce stem cell programs. These effects are restricted to immature HSPC populations, where cohesin mutants show increased chromatin accessibility and likelihood of transcription factor binding site occupancy by HSPC regulators including ERG, GATA2, and RUNX1, as measured by ATAC-seq and ChIP-seq. Epistasis experiments show that silencing these transcription factors rescues the differentiation block caused by cohesin mutants. Together, these results show that mutant cohesins impair HSPC differentiation by controlling chromatin accessibility and transcription factor activity, possibly contributing to leukemic disease.
journal_name
Cell Stem Celljournal_title
Cell stem cellauthors
Mazumdar C,Shen Y,Xavy S,Zhao F,Reinisch A,Li R,Corces MR,Flynn RA,Buenrostro JD,Chan SM,Thomas D,Koenig JL,Hong WJ,Chang HY,Majeti Rdoi
10.1016/j.stem.2015.09.017subject
Has Abstractpub_date
2015-12-03 00:00:00pages
675-688issue
6eissn
1934-5909issn
1875-9777pii
S1934-5909(15)00424-5journal_volume
17pub_type
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