LINCing SUN Proteins to Tissue Homeostasis and Fibrotic Disease
Date of Award
Fall 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Cell Biology
First Advisor
King, Megan
Abstract
Cells must be able to sense and interpret a wide range of both biochemical and mechanical inputs. While the contributions of cellular adhesions within the plasma membrane in integrating mechanical forces into biochemical signaling pathways are well-appreciated, the role of direct mechanotransduction to the nucleus and its effects on cellular behavior are less clear. Mechanical forces from the cytoskeleton are transmitted directly to the nucleus via Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes that span the nuclear envelope. Given the proximity of LINC complexes to chromatin within the nucleus, it has long been hypothesized that the transmission of force directly to the nucleus can directly regulate gene expression by acting, either directly or indirectly, on chromatin. However, the biological contexts in which this mode of signaling may occur and the underlying molecular mechanisms remain key open questions. Here, I provide evidence for two biological contexts in which mechanotransduction to LINC complexes likely plays a role in shaping the cellular response to its environment and build a model for the mechanisms that underly this mode of signaling. First, I provide evidence that tension on LINC complexes is required to maintain an epidermal progenitor state during epidermal homeostasis. I propose a model in which mechanical forces transmitted from b1 integrins to LINC complexes via the actomyosin cytoskeleton prevents precocious expression of epidermal differentiation genes by maintaining a closed chromatin state at the loci that encode those genes. Second, I show a role for the LINC complex component SUN2 in regulating the progression of injury-induced lung fibrosis. I provide evidence that loss of Sun2 uncouples the establishment of fibroblast contractility and matrix deposition, a key step in fibrosis progression, and leads dysregulated cytokine signaling. Together, my work positions mechanotransduction to LINC complexes as an important mechanism for cells to sense long-term mechanical inputs.
Recommended Citation
Carley, Emma, "LINCing SUN Proteins to Tissue Homeostasis and Fibrotic Disease" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1178.
https://elischolar.library.yale.edu/gsas_dissertations/1178
