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Transcriptional Enhancer Activity of Biochemically Marked Genomic Elements

Citation

DeSalvo, Gilberto (2018) Transcriptional Enhancer Activity of Biochemically Marked Genomic Elements. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/J73E-Y429. https://resolver.caltech.edu/CaltechTHESIS:06112018-020802925

Abstract

Functional genomics aspires to explain how a transcription factor (TF) and its measured biochemical occupancy relates to the enhancer activity of the underlying sequence elements. Tissue-specific TFs exhibit remarkable selectivity and reproducibility in the available genome-wide sequence motifs accessed. A consistent central conclusion is that, irrespective of the element selection criteria used, ~50% of candidate Enhancers score as transcriptionally active in both mouse and human cell types, while the remaining 50% of similarly biochemically marked regions are unable to activate transcription on their own. This finding is based on an integrated comparison of a group of functionally assayed elements containing TF-occupied elements, evolutionarily conserved elements, and TF agnostic elements with hallmark biochemical signatures of known enhancers. Quantitatively, the level of TF occupancy signal was the best predictor of the proportion of active enhancers detected, but overall (and contrary to expectation) it is a weak predictor of the magnitude of enhancer activity readout. In specific cell types, elements can display all of the hallmark signatures of enhancers, but can remain inactively poised prior to a stimulus that either activates them or releases a repressive factor. Against previous expectations these poised occupancy sites, once released, behave comparatively in magnitude of enhancer activity as their counterparts that are only directly accessed upon stimulation. Based on our findings, the vast majority of active enhancers in the genome, including some of the most individually powerful ones, are expected to display relatively modest biochemical signatures. Finally, the combined set of over a hundred genomic regions that lacked biochemical marks, even while containing the motifs known to be necessary to bind the relevant TFs, did not support significant enhancer function. We also found evidence that both enhancer orientation and combinations of relatively closely spaced candidate Enhancers, can yield additive functions, with possible fine tuning of the enhancer activity controlled by the type and the distance between individually accessed motifs. In special cases, these elements might cooperate to recruit stable complexes resulting in a synergistic transcriptional activation, suggesting that both local "super-enhancers" and recruited multi-element combinatorics are likely to play an important role in vivo. These findings provide an expectation for enhancer function in the comprehensive annotations provided by the new ENCODE encyclopedia and may help guide future efforts to define the mechanisms by which enhancer activity is achieved and conferred selectively to target genes. Surprisingly, elements that deeply sample the biochemical occupancy of complex loci, match a random population of selected elements remarkably well. Our findings also indicate that carefully designed and lower throughput approaches, rather than high numerical assays that focus on the outstanding features, will bring widely applicable answers to the remaining questions of how relative enhancers are tuned and how seemingly identical regions at a biochemical and motif level are selected for or against function.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Transcription, Enhancers, Genomic Elements, cis Regulatory Modules
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Biology
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Wold, Barbara J.
Thesis Committee:
  • Sternberg, Paul W. (chair)
  • Rothenberg, Ellen V.
  • Hardison, Ross C.
  • Wold, Barbara J.
  • Davidson, Eric H.
Defense Date:11 June 2018
Record Number:CaltechTHESIS:06112018-020802925
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:06112018-020802925
DOI:10.7907/J73E-Y429
Related URLs:
URLURL TypeDescription
https://doi.org/10.1128/genomeA.00233- 15Related ItemArticle in: Genome Announcements 3.2
https://doi.org/10.1101/gr.136184.111Related ItemArticle in: Genome Research 22.9
ORCID:
AuthorORCID
DeSalvo, Gilberto 0000-0002-8957-1699
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11058
Collection:CaltechTHESIS
Deposited By: Gilberto Desalvo
Deposited On:19 Sep 2018 21:20
Last Modified:04 Oct 2019 00:22

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