WASH is required for the differentiation commitment of hematopoietic stem cells in a c-Myc-dependent manner

Pengyan Xia; Shuo Wang; Guanling Huang; Pingping Zhu; Man Li; Buqing Ye; Ying Du; Zusen Fan

doi:10.1084/jem.20140169

WASH is required for the differentiation commitment of hematopoietic stem cells in a c-Myc-dependent manner

J Exp Med. 2014 Sep 22;211(10):2119-34. doi: 10.1084/jem.20140169. Epub 2014 Sep 15.

Authors

Pengyan Xia¹, Shuo Wang², Guanling Huang¹, Pingping Zhu², Man Li¹, Buqing Ye², Ying Du², Zusen Fan³

Affiliations

¹ Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100049, China.
² Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
³ Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China fanz@moon.ibp.ac.cn.

Abstract

Hematopoiesis is fully dependent on hematopoietic stem cells (HSCs) that possess the capacity to self-renew and differentiate into all blood cell lineages. WASH, Wiskott-Aldrich syndrome protein (WASP) and SCAR homologue (WASH) is involved in endosomal sorting as an actin-nucleating protein. Here, we show that conditional WASH deletion in the hematopoietic system causes defective blood production of the host, leading to severe cytopenia and rapid anemia. WASH deficiency causes the accumulation of long-term (LT)-HSCs in bone marrow and perturbs their differentiation potential to mature blood lineages. Importantly, WASH is located in the nucleus of LT-HSCs and associates with the nucleosome remodeling factor (NURF) complex. WASH assists the NURF complex to the promoter of c-Myc gene through its VCA domain-dependent nuclear actin nucleation. WASH deletion suppresses the transcriptional activation of c-Myc gene and impairs the differentiation of LT-HSCs. WASH acts as an upstream regulator to modulate c-Myc transcription for hematopoietic regulation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / physiology*
Cell Line
Chromatin Immunoprecipitation
DNA Primers / genetics
Flow Cytometry
Fluorescent Antibody Technique
Gene Expression Profiling
Gene Expression Regulation / physiology*
Hematopoiesis / physiology*
Hematopoietic Stem Cells / cytology*
Hematopoietic Stem Cells / physiology
Immunoprecipitation
Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism*
Mice
Mice, Knockout
Microarray Analysis
Microfilament Proteins / deficiency
Microfilament Proteins / genetics
Microfilament Proteins / metabolism*
Microscopy, Confocal
Proto-Oncogene Proteins c-myc / metabolism*
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Two-Hybrid System Techniques
Vesicular Transport Proteins / deficiency
Vesicular Transport Proteins / genetics
Vesicular Transport Proteins / metabolism*

Substances

DNA Primers
Microfilament Proteins
Myc protein, mouse
Proto-Oncogene Proteins c-myc
Vesicular Transport Proteins
WASH protein, mouse
Mi-2 Nucleosome Remodeling and Deacetylase Complex