Pbrm1 Steers Mesenchymal Stromal Cell Osteolineage Differentiation by Integrating PBAF-Dependent Chromatin Remodeling and BMP/TGF-β Signaling

Abstract

Summary: Bone morphogenic protein (BMP)/transforming growth factor β (TGF-β) signaling determines mesenchymal-stromal-cell (MSC) osteolineage commitment and tissue identity. However, molecular integration of developmental signaling with MSC-intrinsic chromatin regulation remains incompletely understood. SWI/SNF-(BAF) is an ATP-dependent chromatin remodeler implicated in multi-cellular development. We show that BMPs and long-term osteogenic signals in MSCs selectively induce expression of polybromo BAF (PBAF) components Pbrm1, Arid2, and Brd7. Loss of Pbrm1/Arid2/Brd7 profoundly impairs osteolineage gene expression and osteogenesis without compromising adipogenesis. Pbrm1 loss attenuates MSC in vivo ossification. Mechanistically, Pbrm1/PBAF deficiency impairs Smad1/5/8 activation through locus-specific epi-genomic remodeling, involving Pbrm1 bromodomains, along with transcriptional downregulation of Bmpr/TgfβrII affecting BMP-early-responsive gene expression. Gain of function of BmprIβ, TgfβrII in PBAF-deficient MSCs partly restores Smad1/5/8 activation and osteogenesis. Pbrm1 loss further affects hematopoietic stem and progenitor activity through non-cell-autonomous regulation of microenvironment and niche-factor expression. Together, these findings reveal a link illustrating epi-genomic feedforward control of BMP/TGF-β signaling to transcriptional and cellular plasticity in the mesenchymal microenvironment and account for stromal-SWI/SNF in hematopoiesis. : Sinha et al. examine the role of Pbrm1/polybromo-BAF in mammalian mesenchymal stromal cell osteolineage commitment and hematopoiesis. Osteogenic signals induce Pbrm1/PBAF expression, which in turn orchestrates chromatin remodeling at BmprIβ/TgfβrII loci. These findings reveal an epi-genomic connection to feedforward control of BMP/TGF-β signaling in the mesenchymal stromal microenvironment. Keywords: BMP/TGF-β signaling, mesenchymal stromal cell, hematopoietic microenvironment, hematopoiesis, osteolineage differentiation, SWI/SNF, chromatin remodeling, bromodomain, transcriptional regulation, feedforward control