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Compact Topologies Underlie Long-Range Shh Enhancer-Promoter Communication in the Mouse Embryonic Forebrain / Jailynn A Harke.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Harke, Jailynn A., author.
- Language:
- English
- Subjects (All):
- Genetics.
- Cellular biology.
- Molecular biology.
- Developmental biology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Genetics.
- Cellular biology.
- Molecular biology.
- Developmental biology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Physical Description:
- 1 online resource (130 pages)
- Distribution:
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Contained In:
- Dissertations Abstracts International 85-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Language Note:
- English
- Summary:
- Developmental gene regulation requires input from enhancers spread over large genomic distances. Communication between long-range enhancers and their cognate promoter (E-P) can be identified by orthogonal methods. Sequencing-based approaches (i.e. Hi-C) detect E-P high-frequency interactions between pairs of loci. Imaging-based methods (i.e. FISH) reveal physical proximity between distal E-P elements. Together, a simple looping model emerged whereby the distal elements interact regardless of the intervening chromatin organization. However, both techniques struggle to detect or assign multiway interactions to individual alleles, hindering our understanding of locus topology and how long-range E-P communication may operate. Here, we examine the topology of the entire Shh regulatory domain in individual alleles from the mouse embryonic forebrain. Through sequential Oligopaint labeling and multiple super-resolution microscopy modalities, we assessed the overall Shh locus morphology, individual allele configurations, and specific E-P interactions. We find that the Shh locus maintains a compact structure and adopts several configurations independent of Shh expression. Fluctuations within the compact configuration resulted in enriched distal E-P contacts at the expense of those more proximal to Shh, consistent with an interconnected loop. Genetic perturbations to cis-regulatory elements demonstrate that this long-range E-P communication operates by Shh expression-dependent and independent mechanisms, involving active enhancers and CTCF binding sites, respectively. We propose a Two-Factor Authentication model whereby gene regulatory elements secure long-range E-P interactions amid an inherent architectural framework to coordinate gene expression. By requiring two inputs, the locus safeguards itself against aberrant gene expression while sampling the different configurations. We postulate that the sampling allows loci to respond to widespread regulatory inputs. We predict that other developmental loci may uphold these behaviors as they sense complex enhancer regulation across space and time. This work provides valuable insights into the mechanisms governing developmental gene regulation.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-08, Section: B.
- Advisors: Joyce, Eric F.; Epstein, Douglas J.; Zaret, Kenneth S.; Committee members: Lakadamyali, Melike; Zhou, Zhaolan; Little, Shawn C.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2023.
- Local Notes:
- School code: 0175
- ISBN:
- 9798381509861
- Access Restriction:
- Restricted for use by site license.
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