Chromatin remodeling mediated by ARID1A is indispensable for normal hematopoiesis in mice

Lin Han,Vikas Madan,H Phillip Koeffler,Ienglam Lei,Zhong Wang,Anand Mayakonda,Zeya Cao,Teoh Weoi Woon,Pushkar Dakle,Janani Sundaresan,Pavithra Shyamsunder,Hazimah Binte Mohd Nordin

doi:10.1038/s41375-019-0438-4

Abstract

Precise regulation of chromatin architecture is vital to physiological processes including hematopoiesis. ARID1A is a core component of the mammalian SWI/SNF complex, which is one of the ATP-dependent chromatin remodeling complexes. To uncover the role of ARID1A in hematopoietic development, we utilized hematopoietic cell-specific deletion of Arid1a in mice. We demonstrate that ARID1A is essential for maintaining the frequency and function of hematopoietic stem cells and its loss impairs the differentiation of both myeloid and lymphoid lineages. ARID1A deficiency led to a global reduction in open chromatin and ensuing transcriptional changes affected key genes involved in hematopoietic development. We also observed that silencing of ARID1A affected ATRA-induced differentiation of NB4 cells, suggesting its role in granulocytic differentiation of human leukemic cells. Overall, our study provides a comprehensive elucidation of the function of ARID1A in hematopoiesis and highlights the central role of ARID1A-containing SWI/SNF complex in maintaining chromatin dynamics in hematopoietic cells.

Highlights

Hematopoiesis is a tightly regulated process that constantly generates enormous numbers of mature blood cells through a cascade of differentiation stages
Mx1-Cre model, cellularity was determined 4 weeks after injection of poly(I:C). b Representative staining for LT-hematopoietic stem cells (HSC), ST-HSC and MPP populations using CD34 and Flt3 antibodies in bone marrow (BM) of Arid1af/f;Mx1Cre+ and Arid1af/f;Mx1-Cre– mice, four weeks after poly(I:C) injection. c Proportion of CD34–Flt3– Lin− Sca1+Kit+ (LSK) cells in BM of Arid1a deficient and control mice (n = 5 for Vav-iCre; n = 6 for Mx1-Cre). d Percentage of CD150+CD48− LSK cells in BM of Arid1af/f;Mx1-Cre+ and Arid1af/f;Mx1-Cre− mice, four weeks after poly(I:C) injection (n = 4). e Heat map depicts differential expression of known regulators of hematopoiesis affected by loss of ARID1A in long-term HSCs (LTHSCs)
LTHSC were sorted from the BM of Arid1af/f; Mx1-Cre+ and Arid1af/f;Mx1-Cre− mice, 4 weeks after poly(I:C)

Summary

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Hematopoiesis is a tightly regulated process that constantly generates enormous numbers of mature blood cells through a cascade of differentiation stages. ARID1A (BAF250a) is a principal component of SWI/ SNF (SWItch/Sucrose Non-Fermentable) family of evolutionary conserved, multi-subunit chromatin remodeling complexes. Rearrangements of chromatin structure mediated by SWI/SNF complexes are critical for modulation of gene expression, thereby, affecting a broad range of cellular processes, including proliferation and differentiation [2,3,4,5]. ARID1A resides exclusively in the BAF subclass of SWI/ SNF remodelers and contains an ARID domain, which interacts with DNA in a sequence-nonspecific manner. Our results illustrate that ARID1A maintains frequency and quiescence of HSCs, and regulates differentiation of both myeloid and lymphoid lineages in a cell-intrinsic manner. Depletion of ARID1A leads to extensive decrease in chromatin accessibility including loss of open chromatin at promoter/enhancer regions of several key regulators of hematopoietic development

Materials and methods

Results

Discussion

Compliance with ethical standards