Epigenetic Regulation Controls Intrinsic and Extrinsic Drivers of Gastrointestinal Development

Gastrointestinal development begins with the formation of a featureless tube known as the primitive gut tube. Endodermal cells lining the inside of the gut tube differentiate into the functional epithelial units of the gastrointestinal system. Mesodermal cells surround the endodermal layer and eventually develop into an array of mesenchymal cells which support epithelial function. Development and maturation of the primitive gut tube into the structurally and functionally unique organs of the gastrointestinal system requires highly specific spatial and temporal patterns of gene expression. However, it remains unclear what forces regulate spatiotemporal gene expression patterns in the early gut. Epigenetic control of gene expression offers a possible mechanism for orchestrating the necessary gene expression patterns, but very little is known about how epigenetic forces regulate gut development. In this thesis, I first investigated how intrinsic epigenetic mechanisms influence gut development by mapping the genome-wide chromatin accessibility profile of the developing gut tube at a single-cell resolution, revealing that at the level of chromatin, individual cells are primed to acquire specific lineage fates. I further mapped epigenetic changes throughout gut development, demonstrating how each organ leverages a unique suite of chromatin accessibility patterns and transcription factors (TFs) to reinforce lineage fate decisions. I further showed that loss of the foregut and hindgut lineage-specific TFs, Sox2 and Cdx2, leads to fate shifts in chromatin accessibility patterns, linking TFs, accessibility, and lineage fate decisions in gut development. Finally, I demonstrated that Sox2 overexpression in early development induces pancreatic transformation into foregut precursors. Further, I investigated how epigenetic forces control extrinsic regulators of lineage fate decisions, specifically intercellular communication. Here, I show that mesenchymal cells control epithelial fate and function through Polycomb Repressive Complex 2 (PRC2)-mediated chromatin bivalency. While key lineage-determining genes possess tissue-specific patterns of chromatin accessibility, PRC2 controls WNT ligand expression in mesenchymal cells without altering accessibility. Reduction of mesenchymal WNT secretion rescues organ fate and proliferation defects caused by PRC2 loss. Collectively, my work highlights how epigenetic mechanisms are critical regulators of gastrointestinal development, functioning intrinsically and extrinsically to regulate gene expression patterns required for lineage fate decisions.

Department dc:contributor.department

Molecular Genetics

Year dc:date.issued

2021

Author dc:creator

• Smith, Ryan Joseph

Advisor dc:contributor.advisor

• Kim, Tae-Hee

• Chromatin Accessibility
• Epigenetics
• Gastrointestinal Development
• Intercellular Communincation
• Lineage Fate Decisions
• Transcription Factors

Handle dc:identifier.uri

http://hdl.handle.net/1807/130766

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/130766