Universität zu Köln

Wang, Nini (2026). Gene regulatory programs underlying regenerative competence and stress resilience in the naked mole-rat heart. PhD thesis, Universität zu Köln.

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Abstract

Unlike certain vertebrates such as zebrafish, which retain robust cardiac regeneration throughout life, mammalian hearts have only a transient regenerative window that is lost during postnatal maturation. This process is accompanied by cardiomyocyte cell-cycle exit, metabolic reprogramming, and a marked decline in proliferative capacity. The naked mole-rat (NMR; Heterocephalus glaber) displays unique cardiac features, including resistance to hypoxia and ischemic injury, retention of fetal-like metabolic characteristics, and regenerative ability following myocardial injury. However, the molecular basis of these distinctive cardiac traits remains poorly understood. In this thesis, we investigated the genetic and epigenetic mechanisms underlying the unique cardiac phenotype of NMR using integrative multi-omics analyses and cross-species comparisons with mouse hearts. Our results revealed reduced postnatal remodeling in NMR hearts, accompanied by the persistence of neonatal-like molecular programs. In addition, integrative analysis of transcriptomic and histone ChIP-seq data further identified differentially regulated genes (DRGs) associated with coordinated changes in cis-regulatory elements. These regulatory programs drive cell-cycle-related processes, cytoskeletal remodeling, and metabolic rewiring characterized by reduced fatty acid oxidation (FAO), enhanced glycogen-dependent glycolysis, and redirection of fatty acid utilization from FAO and lipid storage toward phospholipid anabolism. Motif enrichment and DNA footprinting analyses identified estrogen-related receptors (ERRs) as key regulators of this metabolic rewiring. Furthermore, ERBB2 was identified as a neonatal-like regenerative driver that is maintained at the transcriptional, epigenetic, and protein levels in adult NMR hearts but is absent in adult mouse hearts. ERBB2 phosphorylation was further increased following cardiac injury, suggesting sustained ERBB2 signaling that may contribute to the regenerative competence of adult NMR hearts. Under hypoxic conditions, adult NMR hearts adopted an even more neonatal-like transcriptional profile, accompanied by activation of regeneration- and extracellular matrix-related genes, potentially through reactivation of bivalent chromatin states. Collectively, our findings uncover the regulatory basis of the unique cardiac phenotype and stress adaptation of the adult NMR heart, providing mechanistic insights into evolutionary cardiac adaptation and establishing a foundation for strategies to promote cardiac regeneration in adult mammals.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Wang, Nini nini.wang@uk-koeln.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-813967
Date:	2026
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language Nake mole-rat UNSPECIFIED Epigenetic UNSPECIFIED Heart UNSPECIFIED
Date of oral exam:	1 October 2026
Referee:	Name Academic Title Schwarz, Günter Prof. Dr. Reznick, Jane Dr. Beyer, Andreas Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81396