Innovative approaches to identify regulators of liver regeneration / Amber Weiching Wang.

Format:

Book

Thesis/Dissertation

Author/Creator:

Wang, Amber Weiching, author.

Contributor:

University of Pennsylvania. Department of Pharmacology, degree granting institution.

Kaestner, Klaus H., degree supervisor.

Language:

English

Subjects (All):

Genetics.

Bioinformatics.

Systematic biology.

Pharmacology--Penn dissertations.

Penn dissertations--Pharmacology.

Local Subjects:

Genetics.

Bioinformatics.

Systematic biology.

Pharmacology--Penn dissertations.

Penn dissertations--Pharmacology.

Genre:

Academic theses.

Physical Description:

1 online resource (216 pages)

Contained In:

Dissertations Abstracts International 81-08B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2019.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

The mammalian liver possesses a remarkable ability to regenerate after injury to prevent immediate organ failure. However, amid a rising global burden of liver disease, the only curative treatment for patients with end-stage liver disease is transplantation. Elucidating the mechanisms underlying tissue repair and regrowth will enable identification of therapeutic targets to stimulate native liver regeneration, thereby circumventing the great paucity of available transplant organs. Here, utilizing the Fah-/- mouse model of liver repopulation, I applied transcriptomic and epigenomic techniques to investigate the changes occurring as hepatocytes restore organ mass following toxic injury. By labeling ribosomal or nuclear envelope proteins, I performed the first extensive characterization of gene expression and chromatin landscape changes specifically in repopulating hepatocytes in response to injury. Transcriptomic analysis showed that repopulating hepatocytes highly upregulate Slc7a11, a gene that encodes the cystine/glutamate antiporter. I demonstrated that ectopic Slc7a11 expression promotes liver regeneration and Slc7a11 mutation inhibits hepatocyte replication. Integrative bioinformatics analyses of chromatin accessibility revealed dynamic changes at promoters and liver-enriched enhancer regions that correlate with the activation of proliferation-associated genes and the repression of transcripts expressed in mature, quiescent hepatocytes. Furthermore, changes in chromatin accessibility and gene expression are associated with increased promoter binding of CCCTC-binding factor (CTCF) and decreased enhancer occupancy of hepatocyte nuclear factor 4α (HNF4α). In summary, my thesis work identifies Slc7a11 as a potential driver of liver regeneration, and provides insights into the complex crosstalk between chromatin accessibility and transcription factor occupancy to regulate gene expression in repopulating hepatocytes.

Notes:

Source: Dissertations Abstracts International, Volume: 81-08, Section: B.

Includes supplementary digital materials.

Advisors: Kaestner, Klaus H.; Committee members: Mitchell Lazar; Michael Pack; Benjamin Voight; Kirk Wangensteen.

Department: Pharmacology.

Ph.D. University of Pennsylvania 2019.

Local Notes:

School code: 0175

ISBN:

9781392699621

Access Restriction:

Restricted for use by site license.

This item must not be sold to any third party vendors.