Advisor(s)
Yang Zhou
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Joint Health Sciences
Date of Award
9-11-2025
Abstract
Histone deacetylase complexes play pivotal roles in cardiac biology, however their specific functions in cell fate transitions and adult heart maintenance re-main unclear. We identified the role of HDAC complex in vitro during direct cardiac repro-gramming and in vivo through specific cardiomyocyte deletion of ELMSAN1, a core component of the MiDAC complex. We perform direct cardiac reprogram-ming using a polycistronic construct (hMGT133) expressing MEF2C, GATA4, TBX5, and miR-133. MEF2C expression peaked early, while cardiac markers such as cardiac troponin and α-actinin emerged by Day 9. HDAC1 levels and global histone acetylation (H3K9ac, H3K14ac, H3K27ac) declined over time. An RNAi screen targeting components of four HDAC complexes revealed that most are required for reprogramming efficiency, with SMRT and COREST1 knock-down causing significant cell death. To investigate the in vivo role of ELMSAN1, we generated cardiomyocyte-specific knockout mice (ELM cKO) by crossing Elmsan1-floxed mice with αMHC-Cre+ mice. Efficient deletion of Elmsan1 was confirmed in cardiomyocytes with-out off-target effects. While ELM cKO mice appeared phenotypically normal at young ages (4–8 weeks), they progressively developed dilated cardiomyopathy marked by declining ejection fraction, ventricular dilation, wall thinning, and ele-vated ANP expression. No ELM cKO mice survived beyond 11 months. Tran-scriptomic profiling at 8 weeks revealed downregulation of calcium-handling genes (e.g., RYR2, ATP2A2, PLN) and mitochondrial regulators (e.g.,PPARα, PGC1α). Mitochondrial defects were further confirmed by reduced respiratory chain proteins, altered ultrastructure on TEM, and impaired expression of TCA cycle genes. These data demonstrate that ELMSAN1 is indispensable for adult cardiac function through transcriptional regulation of metabolic and contractile genes. Loss of ELMSAN1 induces progressive heart failure, identifying it as a key regulator in age-dependent cardiomyopathy.
ProQuest ID
Recommended Citation
Wang, Meimei, "The Role Of Histone Deacetylase Complexes In Cardiomyocyes And Heart Diseases" (2025). All ETDs from UAB. 7353.
https://digitalcommons.library.uab.edu/etd-collection/7353
