Chromatin Reorganization during Myoblast Differentiation Involves the Caspase-Dependent Removal of SATB2.

Ryan A V Bell,Georg Dechant,Alphonse Chu,Steve Brunette,F Jeffrey Dilworth,Lynn A Megeney,Dalal Alsowaida,Galina Apostolova,Mohammad H Al-Khalaf,Hina Bandukwala

doi:10.3390/cells11060966

Abstract

The induction of lineage-specific gene programs are strongly influenced by alterations in local chromatin architecture. However, key players that impact this genome reorganization remain largely unknown. Here, we report that the removal of the special AT-rich binding protein 2 (SATB2), a nuclear protein known to bind matrix attachment regions, is a key event in initiating myogenic differentiation. The deletion of myoblast SATB2 in vitro initiates chromatin remodeling and accelerates differentiation, which is dependent on the caspase 7-mediated cleavage of SATB2. A genome-wide analysis indicates that SATB2 binding within chromatin loops and near anchor points influences both loop and sub-TAD domain formation. Consequently, the chromatin changes that occur with the removal of SATB2 lead to the derepression of differentiation-inducing factors while also limiting the expression of genes that inhibit this cell fate change. Taken together, this study demonstrates that the temporal control of the SATB2 protein is critical in shaping the chromatin environment and coordinating the myogenic differentiation program.

Highlights

One of the key alterations that characterize a cell’s progression through differentiation is the restructuring of the nuclear landscape to allow for the expression of lineage-specific genes
special AT-rich binding protein 2 (SATB2) was mainly relegated to the euchromatic nuclear space; there was a significant subfraction of SATB2 co-staining with heterochromatin protein 1α (HP1α) occurring in the more condensed regions of the nucleus, which declined as the differentiation program proceeded (Figure 1C)
Having established that the SATB2 protein is reduced during myogenesis, we sought to determine the role of SATB2 in muscle cell proliferation and differentiation

Summary

Introduction

One of the key alterations that characterize a cell’s progression through differentiation is the restructuring of the nuclear landscape to allow for the expression of lineage-specific genes. Chromatin conformation undergoes significant restructuring when cells progress from replicating to differentiating phenotypes, with changes occurring to repress or open access at specific gene loci [1,2]. These genome alterations are facilitated by two general mechanisms—loci-specific modifications of DNA and histones and the targeting of structural proteins that control the higher-order structure of chromatin [3,4]. MAR binding proteins are unique in that they integrate both repressive and inductive signals for gene expression, a feature that would be valuable for the management of cell fate transitions This duality of MAR protein function depends on the proximity of gene promoters and insulator regions relative to the position where the MAR protein anchors the DNA to the chromatin scaffold [7,8]. Scaffold attachment factor b1 (Safb1) has been shown to activate pro-differentiation gene expression in skeletal muscle cells, yet it does not appear to directly repress the expression of genes in muscles [9]

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Results

Conclusion