GSBS Dissertations and Theses

ORCID ID

0000-0003-4000-7891

Publication Date

2020-04-14

Document Type

Doctoral Dissertation

Academic Program

Interdisciplinary Graduate Program

Department

Bioinformatics and integrative biology

First Thesis Advisor

Manuel Garber

Keywords

Gene expression regulation, chromatin, 3D genome, enhancers, promoters, cis-regulation, transcription factors, the evolution of gene expression regulation, conservation, innate immune cells, temporal transcription

Abstract

Transcriptional regulation is the principal mechanism in establishing cell-type specific gene activity by exploring an almost infinite space of different combinations of regulatory elements, transcription factors with high precision. Recent efforts have mapped thousands of candidate regulatory elements, of which a great portion is cell-type specific yet it is still unclear as to what fraction of these elements is functional, what genes these elements regulate, or how they are established in a cell-type specific manner. In this dissertation, I will discuss methods and approaches I developed to better understand the role of regulatory elements and transcription factors in gene expression regulation.

First, by comparing the transcriptome and chromatin landscape between mouse and human innate immune cells I showed specific gene expression programs are regulated by highly conserved regulatory elements that contain a set of constrained sequence motifs, which can successfully classify gene-induction in both species. Next, using chromatin interactions I accurately defined functional enhancers and their target genes. This fine mapping dramatically improved the prediction of transcriptional changes. Finally, we built a supervised learning approach to detect the short DNA sequences motifs that regulate the activation of regulatory elements following LPS stimulation. This approach detected several transcription factors to be critical in remodeling the epigenetic landscape both across time and individuals.

Overall this thesis addresses several important aspects of cis-regulatory elements in transcriptional regulation and started to derive principles and models of gene-expression regulation that address the fundamental question: “How do cis-regulatory elements drive cell-type-specific transcription?”

Comments

Dr. Pranitha Vangala was a recipient of the 2020 GSBS Dean's Award for outstanding doctoral thesis research.

DOI

10.13028/rd6e-hv37

Rights and Permissions

Licensed under a Creative Commons license

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This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

Available for download on Thursday, May 27, 2021

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