Excellence in Research: Molecular characterization of the TLE1-mediated transcriptional and epigenetic program as a modulator of epithelial cell survival and a target of integrins

Xavier University Of Louisiana, New Orleans LA

Investigators

Abstract

Cells on the surface of animal tissues and organs adhere for survival to an underlying extracellular matrix (ECM) of proteins via adhesion proteins called integrins. Loss of cell attachment is regulated to shed cells from these tissues via a process called programmed cell death. While direct integrin-mediated signals to downstream cell death processes are well characterized, little is known about other integrin-regulated mechanisms that affect or prevent programmed cell death. This project aims to understand the role of an integrin-mediated protein called TLE1, which works as a master regulator of integrin-mediated cell survival via TLE1’s effects on activation of many genes. The research plan is to characterize these downstream gene targets of TLE1, as well as components of the other proteins that work with TLE1 in order to better understand the regulation of the balance between cell survival and death, which is essential for development and maintenance of organisms. By advancing knowledge of the regulation of cell death, this project may yield novel therapeutic strategies that target cell death pathways in order to advance or prevent removal of cells for disease treatment. Additionally, this project expands the research capability at Xavier University of Louisiana and supports education and broadening participation for undergraduate students by integrating systems biology research into undergraduate courses and providing research opportunities for undergraduate students. The project will generate crucial insights into the transcriptional and epigenetic mechanisms governing epithelial cell survival. Specifically, it will explore the role of transcriptional coregulators as molecular targets of integrins in fine-tuning epigenetic and transcriptional responses. Using multiomics and bioinformatic approaches, this project aims to: i) Identify the survival-promoting gene transcriptional program controlled by TLE1 and integrin-regulated cell adhesion via integrated RNA-seq and ChIP-seq analysis; ii) Characterize the key components of the TLE1 corepressor complex that drive transcriptional and epigenetics events underpinning epithelial cell survival through proteomics; and iii) Map the TLE1-dependent genome-wide histone marks associated with epithelial cell survival by use of epigenetic and epigenomic approaches. Leveraging integrated multiomics data analysis coupled with molecular, biochemical, and cellular validation, this project will underscore the role of TLE1 in defining an epigenetic signature permissive of gene expression critical for adhesion-dependent cell survival. Inhibition of TLE1’s nuclear function upon loss of integrin-dependent survival signal may result in an epigenomic landscape associated with cell death. The research findings will provide a mechanistic framework for the role of transcriptional coregulators in linking epigenome alterations to transcriptional reprogramming during cellular stress. This work will also have significant impact on understanding animal tissue homeostasis and organismal development, as both processes require precise regulation of epithelial cell survival and death. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.