Date on Master's Thesis/Doctoral Dissertation

8-2023

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, MS

Committee Chair

Mohamed, Tamer M.

Committee Co-Chair (if applicable)

Siskind, Leah J.

Committee Member

Siskind, Leah J.

Committee Member

Jones, Steven P.

Committee Member

Clark, Geoffrey J.

Author's Keywords

Cardiac regeneration; cardiomyocyte; heart failure; myocardial infarctionEpigenetic

Abstract

The limited regenerative capacity of adult cardiomyocytes (CMs) is manifested in prevalent morbidity and mortality associated with ischemic heart disease. We previously demonstrated that a combination of four cell cycle factors (4F) promotes efficient cell division in differentiated CMs. The temporal transcriptional reprogramming in the 4F-transduced CMs indicates that epigenetic modifications mediate the cell cycle progression. Through small molecule screening, we evaluated the epigenetic impact on CM’s response in the 4F-transduced CMs. We identified the histone demethylase 5B (KDM5B), which through in vitro and ex vivo genetic knockdown and overexpression studies, exhibited a modulative effect on CM’s cell cycle plasticity along with transcriptional alteration in the cell cycle-related genes. Whereas KDM5B depletion impaired CM’s replicative capacity, its overexpression induced and augmented CM’s proliferation in a context-dependent manner. Our data indicate that KDM5B is essential for CM’s regeneration and cell cycle activation and is a potential target for myocardial repair.

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