Muscle progenitor specification and myogenic differentiation are associated with changes in chromatin topology

Abstract

Using Hi-C, promoter-capture Hi-C (pCHi-C), and other genome-wide approaches in skeletal muscle progenitors that inducibly express a master transcription factor, Pax7, we systematically characterize at high-resolution the spatio-temporal re-organization of compartments and promoter-anchored interactions as a consequence of myogenic commitment and differentiation. We identify key promoter-enhancer interaction motifs, namely, cliques and networks, and interactions that are dependent on Pax7 binding. Remarkably, Pax7 binds to a majority of super-enhancers, and together with a cadre of interacting transcription factors, assembles feed-forward regulatory loops. During differentiation, epigenetic memory and persistent looping are maintained at a subset of Pax7 enhancers in the absence of Pax7. We also identify and functionally validate a previously uncharacterized Pax7-bound enhancer hub that regulates the essential myosin heavy chain cluster during skeletal muscle cell differentiation. Our studies lay the groundwork for understanding the role of Pax7 in orchestrating changes in the three-dimensional chromatin conformation in muscle progenitors.

Major Reorganization of Chromosome Conformation During Muscle Development in Pig

“…In addition, the anatomical, physiological and genetic homologies between human and pig also make it of interest for the biomedical field ( Lunney, 2007 ; Meurens et al, 2012 ). Related 3D genomics studies on muscle development were mostly performed on mouse, using in vitro cell cultures ( Doynova et al, 2017 ; He et al, 2018 ; Zhang et al, 2020 ), targeting early stages (myoblasts proliferation and differentiation). Here, we focused on the maturity process of differentiated muscle fibers before birth.…”

Chromatin Conformation in Development and Disease

“…Transcription after activation of the glucocorticoid receptor occurs without significant changes of the pre-looped chromatin interactions, enabling its rapid reaction ( Hakim et al, 2011 ). Changes in chromatin topology and conformation have already been associated and described in muscle progenitor specification and myogenic differentiation ( Zhang et al, 2020 ), sensory experience during post-natal brain development ( Tan et al, 2021 ), dendritic cell development and differentiation ( Chauvistré and Seré, 2020 ), and neural development ( Kishi and Gotoh, 2018 ).…”

Cis-regulatory chromatin loops analysis identifies GRHL3 as a master regulator of surface epithelium commitment

“…Lineage commitment during embryonic stem cell (ESC) differentiation requires chromatin reorganization and lineage-specific gene activation that is orchestrated by cis-regulatory networks (3)(4)(5)(6)(7). Large-scale epigenomic studies have shown that long-range cisregulatory elements coordinate lineage-specific transcriptional programs by looping to their target promoters (5,(8)(9)(10).…”