The Chromatin Remodeler BPTF Activates a Stemness Gene-Expression Program Essential for the Maintenance of Adult Hematopoietic Stem Cells.

Bowen Xu,Rui Lu,Jason M Butler,Ling Cai,Deyou Zheng,Dongliang Chen,Xiongdong Lu,Gang Greg Wang,David F Allison,Joel S Parker,Shahin Rafii

doi:10.1016/j.stemcr.2018.01.020

Abstract

SummarySelf-renewal and differentiation of adult stem cells are tightly regulated partly through configuration of chromatin structure by chromatin remodelers. Using knockout mice, we here demonstrate that bromodomain PHD finger transcription factor (BPTF), a component of the nucleosome remodeling factor (NURF) chromatin-remodeling complex, is essential for maintaining the population size of hematopoietic stem/progenitor cells (HSPCs), including long-term hematopoietic stem cells (HSCs). Bptf-deficient HSCs are defective in reconstituted hematopoiesis, and hematopoietic-specific knockout of Bptf caused profound defects including bone marrow failure and anemia. Genome-wide transcriptome profiling revealed that BPTF loss caused downregulation of HSC-specific gene-expression programs, which contain several master transcription factors (Meis1, Pbx1, Mn1, and Lmo2) required for HSC maintenance and self-renewal. Furthermore, we show that BPTF potentiates the chromatin accessibility of key HSC “stemness” genes. These results demonstrate an essential requirement of the chromatin remodeler BPTF and NURF for activation of “stemness” gene-expression programs and proper function of adult HSCs.

Highlights

Appropriate self-renewal and differentiation of adult stem cells are essential for tissue homeostasis and are tightly controlled by various cellular and molecular mechanisms, including the dynamic regulation of chromatin structure by ATP-dependent chromatin-remodeling complexes (Kadoch and Crabtree, 2015; Wang et al, 2007)
Maintenance of Adult hematopoietic stem/progenitor cells (HSPCs), Including Long-Term hematopoietic stem cells (HSCs), Requires Bptf Expression Using transcriptome datasets of hematopoiesis (Bock et al, 2012; Seita et al, 2012), we found Bptf preferentially expressed in the primitive HSPC compartment (Figures 1A, S1A, and S1B)
While Mx1-cre is widely used for achieving inducible gene deletion in HSPC, it is associated with polyinosinic-polycytidylic acid (pIpC)-caused interferon activation and cre-induced potential toxicity

Summary

Introduction

Appropriate self-renewal and differentiation of adult stem cells are essential for tissue homeostasis and are tightly controlled by various cellular and molecular mechanisms, including the dynamic regulation of chromatin structure by ATP-dependent chromatin-remodeling complexes (Kadoch and Crabtree, 2015; Wang et al, 2007). These remodelers use energy produced from ATP hydrolysis to configure nucleosomal positioning and modulate DNA accessibility. While previous works detail the essential role for KMT2A in regulation of hematopoietic and neuronal stem cells (Artinger et al, 2013; Jude et al, 2007; Lim et al, 2009), the specific contributions of BPTF remain undefined in this process

Results

Discussion

Conclusion