Mechanical Signaling mediated 3D chromatin remodeling in stem cell fate

University Of North Dakota, Grand Forks ND

Investigators

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Abstract

Skeletal muscle tissue resident stem cells, also called Satellite cells, play a vital role in the repair and regeneration of skeletal muscle tissue. The adult SCs exist in a non-dividing quiescent state. Upon muscle injury, the SCs rapidly exit quiescence, activate, proliferate and differentiate to form new muscle. A failure in the regenerative process results in muscle diseases such as dystrophies, laminopathies and aging. The initial transition from quiescence to activation represents a critical step to enhance regeneration of the muscle tissue. The molecular drivers that transform the quiescent SCs into actively dividing stem cells is largely unknown. These mechanisms of quiescence and activation rely on tissue specific transcription factors, chromatin remodelers and higher order chromatin organization to modulate tissue specific gene expression. The long-term goal of my laboratory is to study the influence of higher order chromatin structure on SC quiescence to activation fate determination. The objective of this proposal is to determine the Wnt4/RhoA (mechanical signaling) mediated 3D chromatin remodeling in stem cell fate. Here, our central hypothesis is Wnt4-RhoA signaling pathway regulates nuclear and chromatin dynamics, thereby influencing skeletal muscle stem cell fate and cellular processes of adhesion and migration. The central hypothesis will be tested by three specific aims: 1) Determine how Wnt4 -RhoA signaling pathway regulates the expression of YAP in SCs. 2) Determine the role of Wnt4-RhoA signaling pathway on chromatin remodeling, thereby affecting SC fate. 3) Explore the mechanism by which nuclear Lamin A/C couples nuclear shape and size with cellular processes. This proposal is innovative, as we are pursuing novel unexplored links between 1) the non-canonical Wnt4-RhoA cytoskeletal signaling pathway and chromatin remodeling in quiescent SCs, 2) YAP1 and remodeling of the genomic landscape in activated SCs, and 3) the functional role of Lamin AC in adhesion and migration of SCs. Understanding the higher order chromatin structure and identifying the molecules that regulate the chromatin landscape enabling the transition between quiescence and activation, will have a significant impact on therapeutically improving tissue regeneration in various muscle pathologies and in aging.