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Genomic Basis for the Circadian Regu...

Weidemann, Benjamin.

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Genomic Basis for the Circadian Regulation of Beta-Cell Function and Glucose Homeostasis.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Genomic Basis for the Circadian Regulation of Beta-Cell Function and Glucose Homeostasis./
Author:	Weidemann, Benjamin.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
Description:	173 p.
Notes:	Source: Dissertations Abstracts International, Volume: 85-06, Section: B.
Contained By:	Dissertations Abstracts International85-06B.
Subject:	Endocrinology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30694491
ISBN:	9798381175189

Genomic Basis for the Circadian Regulation of Beta-Cell Function and Glucose Homeostasis.
Weidemann, Benjamin.

Genomic Basis for the Circadian Regulation of Beta-Cell Function and Glucose Homeostasis. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 173 p.

Source: Dissertations Abstracts International, Volume: 85-06, Section: B.

Thesis (Ph.D.)--Northwestern University, 2023.

In mammals, the central pacemaker clock synchronizes peripheral tissue clocks in anticipation of environmental queues. Epidemiologic and genetic studies in mammals demonstrate that the 24-hour transcriptional core clock feedback loop is essential for healthful behavior and the mitigation of metabolic disease. Our laboratory previously characterized transcriptional rhythms underlying daily function of the pancreatic islet, a life-requiring tissue that undergoes circadian patterns in RNA synthesis and glucose-mediated insulin exocytosis. The core circadian transcription factors regulate genome activity through phasic recruitment of chromatin coregulators, yet how clock factors are integrated with cell-defining programs to align energy utilization with nutrient availability is not well understood. Here, using novel single-cell and chromatin-sequencing tools that reveal the chromatin basis underlying circadian function and cell identity, I identified unique β-cell subtypes defined by distinct circadian and functional molecular signatures. Using mouse genetics and circadian manipulation of both live human and mouse islet tissue I characterized the relationship between a β-cell master regulator, the pancreatic duodenal homeobox 1 (PDX1) transcription factor, and the inflammatory modulator NF-κB. Interplay between these factors drives both circadian function and cellular identity. Pharmacological intervention using the interleukin 1β antagonist can bypass the secretory defect imparted by PDX1 deficiency, revealing a genetic basis for treatment of disease with an inflammatory component. Additional studies in circadian mutant cells, which recapitulate β-cell failure in type 2 diabetes, established a genomic basis for how the circadian clock promotes energy constancy throughout life. Development of a novel assay for cost-effective assessment of insulin secretory capacity revealed additional pathways that can bypass circadian insulin defects, while transcriptional analysis in circadian mutants revealed shared networks of alternatively spliced exocytic genes with those altered in the islets of diet-induced obesity rodent models, demonstrating shared regulation by circadian factors and the environment at the level of signal transduction and splicing. Together the studies presented in this thesis reveal circadian mechanisms that dictate whole-body metabolism, and reveal novel therapeutic targets for enhancing β-cell function in the context of circadian pathway disruption.

ISBN: 9798381175189Subjects--Topical Terms:

610914
Endocrinology.
Subjects--Index Terms:

Beta cell

Genomic Basis for the Circadian Regulation of Beta-Cell Function and Glucose Homeostasis.
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