Biochemical and Functional Studies of Histone Deacetylase 3 in Metabolic Tissues / Jarrett Renn Remsberg.

Format:

Book

Thesis/Dissertation

Author/Creator:

Remsberg, Jarrett Renn, author.

Contributor:

Lazar, Mitchell A., degree supervisor.

Stoffers, Doris A., degree committee member.

Kohli, Rahul M., degree committee member.

Garcia, Benjamin A., degree committee member.

Birnbaum, Morris J., degree committee member.

University of Pennsylvania. Biochemistry and Molecular Biophysics, degree granting institution.

Language:

English

Subjects (All):

Biochemistry.

Molecular biology.

Biochemistry and Molecular Biophysics--Penn dissertations.

Penn dissertations--Biochemistry and Molecular Biophysics.

Local Subjects:

Biochemistry.

Molecular biology.

Biochemistry and Molecular Biophysics--Penn dissertations.

Penn dissertations--Biochemistry and Molecular Biophysics.

Genre:

Academic theses.

Physical Description:

1 online resource (133 pages)

Contained In:

Dissertation Abstracts International 79-01B(E).

Place of Publication:

[Philadelphia, Pennsylvania]: University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2017.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

Organismal physiology is built upon the foundation of molecular processes. A central axis to maintaining homeostasis in vivo is at the level of gene regulation. Tissue specific gene expression is created at the level of epigenetics, where proteins guided by tissue specific DNA binding proteins create a chromatin landscape for precise gene programs. Understanding these molecular processes is of vital importance to understand the underpinning pathologies, such as metabolic syndrome, which are a growing medical concern and require greater research efforts in order to tackle its challenges. A major epigenetic regulator is histone deacetylase 3 (HDAC3), which is a core member of the nuclear receptor corepressor (NCoR) complex. This ubiquitously expressed chromatin associated protein complex functions to repress target gene transcription. Here we address the functional role of HDAC3 in beta-cells of adult mice. An HDAC3 beta-cells specific knockout was generated using the MIP-CreERT transgenic mouse model and while HDAC3 beta-cells specific deletion did not increase total pancreatic insulin content, the mice demonstrated markedly improved glucose tolerance and increased glucose-stimulated insulin secretion. Cistromic and transcriptomic analyses of pancreatic islets revealed that HDAC3 regulated multiple genes that contribute to glucose-stimulated insulin secretion. Furthermore, using mass spectrometry in conjunction of cistromic analyses of interactors we have characterized the interactome of HDAC3 and detailed its function in mammalian liver. We identified PROX1 as an abundant interactor which is corecruited with HDAC3 by HNF4alpha in liver to corepress gene transcription important for maintenance of lipid homeostasis. Lastly, as we continue to explore the protein-protein interaction networks of these critical factors, novel tools are proving to be invaluable to their investigation. The advent of CRISPR-Cas9 genome editing has allowed for reliable and simple design and generation of mouse models. Therefore we have employed this technology to generate a variety of epitope tagged mouse models with the goal of comparing their tissue specific interactomes. This body of work includes a wide breadth of biological techniques that have succeeded in advancing knowledge of HDAC3 function in vivo, vital to our understanding of molecular pathology in diabetes and obesity.

Notes:

Source: Dissertation Abstracts International, Volume: 79-01(E), Section: B.

Advisors: Mitchell A. Lazar; Committee members: Morris J. Birnbaum; Benjamin A. Garcia; Rahul M. Kohli; Doris A. Stoffers.

Department: Biochemistry and Molecular Biophysics.

Ph.D. University of Pennsylvania 2017.

Local Notes:

School code: 0175

ISBN:

9780355182798

Access Restriction:

Restricted for use by site license.