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

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.

• Authors: Pengyan Xia, Shuo Wang, Guanling Huang, Pingping Zhu, Man Li, Buqing Ye, Ying Du, Zusen Fan
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 211 Issue 10 Pg. 2119-34 (Sep 22 2014) ISSN: 1540-9538 [Electronic] United States
• PMID: 25225459 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Xia et al.

Chemical References

• 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

Topics

• 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, physiology)
• Immunoprecipitation
• Mi-2 Nucleosome Remodeling and Deacetylase Complex (metabolism)
• Mice
• Mice, Knockout
• Microarray Analysis
• Microfilament Proteins (deficiency, genetics, metabolism)
• Microscopy, Confocal
• Proto-Oncogene Proteins c-myc (metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Two-Hybrid System Techniques
• Vesicular Transport Proteins (deficiency, genetics, metabolism)