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The Role of 3D Regulatory Enhancer Landscapes and Enhancer Hubs in Stem Cell Fate Maintenance and Change
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The Role of 3D Regulatory Enhancer Landscapes and Enhancer Hubs in Stem Cell Fate Maintenance and Change
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Dissertation
The Role of 3D Regulatory Enhancer Landscapes and Enhancer Hubs in Stem Cell Fate Maintenance and Change
2024
Overview
Mammalian embryogenesis begins with sequential cell fate decisions giving rise to three essential lineages, the trophectoderm (TE), the epiblast (EPI) and the primitive endoderm (PrE). Key signaling pathways and transcription factors controlling these early embryonic decisions have been identified, but the non-coding regulatory elements via which transcriptional regulators enact these fates remain understudied. We have characterized, at genome-wide scale, enhancer activity and connectivity in embryo-derived stem cell lines representing each early developmental fate, yielding high-resolution 2D and 3D regulatory maps of the first cell fate decisions. We observed extensive enhancer remodeling and fine-scale 3D chromatin rewiring among the three lineages, strongly associating with transcriptional changes. In each lin.age, high degree of connectivity or “hubness” positively correlates with levels and cell-type specificity of gene expression and enriches for essential genes. Genes within 3D hubs also show a significantly stronger probability of coregulation during cell fate transitions, compared to genes in linear proximity or within the same contact domains. By building and testing various computational models of transcriptional regulation; and including specific 3D chromatin features, we were able to outperform models using only 2D promoter or proximal variables in predicting cell-type specific gene expression. Genome-wide in silico perturbations allowed us to nominate candidate functional enhancers in each cell lineage for validation at several relevant genomic loci. Our study comprehensively identifies 3D regulatory hubs associated with the earliest mammalian lineages and describes their relationship to gene expression and cell identity, providing a framework to understand lineage-specific transcriptional behaviors.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9798381684773
