Mechanical Signaling mediated 3D chromatin remodeling in stem cell fate

机械信号介导干细胞命运中的 3D 染色质重塑

• 批准号: 10641134
• 负责人: SUSAN ELIAZER
• 金额: $ 17.17万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10641134
• 关键词: 3-Dimensional; Adhesions; Adult; Affect; Aging; Cell physiology; Centers of Research Excellence; Chromatin; Couples; Development; Disease; Failure; Genomics; Goals; Higher Order Chromatin Structure; Injury; Laboratories; Lamin Type A; Lamins; Link; Mediating; Molecular; Muscle; Myopathy; Natural regeneration; Nuclear; Nuclear Lamin; Pathology; Play; Process; Proliferating; Role; Shapes; Signal Pathway; Skeletal Muscle; Testing; Therapeutic; Tissue-Specific Gene Expression; Tissues; adhesion process; chromatin remodeling; epigenomics; improved; innovation; mechanical signal; migration; muscle regeneration; novel; regenerative; repaired; satellite cell; stem cell fate; stem cells; tissue regeneration; transcription factor

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.

骨骼肌组织驻留干细胞，也称为卫星细胞，在骨骼肌组织的修复和再生中起着至关重要的作用。成体干细胞处于不分裂的静止状态。在肌肉损伤后，SC迅速退出静止期，活化，增殖和分化以形成新的肌肉。再生过程中的失败导致肌肉疾病，如营养不良、核纤层蛋白病和衰老。从静止到激活的初始过渡代表了增强肌肉组织再生的关键步骤。将静止的SC转化为活跃分裂的干细胞的分子驱动因素在很大程度上是未知的。这些静止和激活机制依赖于组织特异性转录因子、染色质重塑剂和更高级染色质组织来调节组织特异性基因表达。本实验室的长期目标是研究高阶染色质结构对SC静止到激活命运决定的影响。本提案的目的是确定Wnt 4/RhoA（机械信号）介导的干细胞命运中的3D染色质重塑。在这里，我们的中心假设是Wnt 4-RhoA信号通路调节核和染色质动力学，从而影响骨骼肌干细胞的命运和粘附和迁移的细胞过程。本研究将通过以下三个具体目标来验证中心假设：1）确定Wnt 4-RhoA信号通路如何调节SC中雅普的表达。2)确定Wnt 4-RhoA信号通路对染色质重塑的作用，从而影响SC命运。3)探索核核纤层蛋白A/C将核形状和大小与细胞过程耦合的机制。该提议是创新的，因为我们正在寻求1）非经典Wnt 4-RhoA细胞骨架信号传导途径和静止SC中的染色质重塑，2）YAP 1和活化SC中基因组景观的重塑，以及3）核纤层蛋白AC在SC粘附和迁移中的功能作用之间的新的未探索的联系。了解更高级的染色质结构并识别调节染色质景观的分子，从而实现静止和激活之间的过渡，将对治疗上改善各种肌肉病理和衰老中的组织再生产生重大影响。