Transcriptional Profiling of Cardiac Cells Links Age-Dependent Changes in Acetyl-CoA Signaling to Chromatin Modifications

Abstract

Metabolism has emerged as a regulator of core stem cell properties such as proliferation, survival, self-renewal, and multilineage potential. Metabolites serve as secondary messengers, fine-tuning signaling pathways in response to microenvironment alterations. Studies show a role for central metabolite acetyl-CoA in the regulation of chromatin state through changes in histone acetylation. Nevertheless, metabolic regulators of chromatin remodeling in cardiac cells in response to increasing biological age remains unknown. Previously, we identified novel cardiac-derived stem-like cells (CTSCs) that exhibit increased functional properties in the neonatal heart (nCTSC). These cells are linked to a unique metabolism which is altered with CTSC aging (aCTSC). Here, we present an in-depth, RNA-sequencing-based (RNA-Seq) bioinformatic with cluster analysis that details a distinct epigenome present in nCTSCs but not in aCTSCs. Gene Ontology (GO) and pathway enrichment reveal biological processes, including metabolism, gene regulation enriched in nCTSCs, and STRING analysis that identifies a network of genes related to acetyl-CoA that can potentially influence chromatin remodeling. Additional validation by Western blot and qRT-PCR shows increased acetyl-CoA signaling and histone acetylation in nCTSCs compared to aCTSCs. In conclusion, our data reveal that the link between metabolism and histone acetylation in cardiac cells is altered with the aging of the cardiac tissue.

UCP2 modulates cardiomyocyte cell cycle activity, acetyl-CoA, and histone acetylation in response to moderate hypoxia

“…In the cardiac context, distinct epigenetic regulating signaling pathways are known to alter in fetal, postnatal and disease CMs (33,34). Our recent study identifies agedependent changes in acetyl-CoA signaling to histone acetylation in cardiac cells (35).…”

“…In the cardiac context, distinct epigenetic regulating signaling pathways are known to be altered in fetal, postnatal, and disease CM ( 33 , 34 ). Our recent study identifies age-dependent changes in acetyl-CoA signaling to histone acetylation in cardiac cells ( 35 ). Nevertheless, the precise role of metabolic signaling pathways and histone acetylation for regulation of CM cell cycle in the heart under hypoxia is largely undetermined.…”

“…Immunoblot analysis was performed as previously described ( 17 , 35 , 36 ), with additional detail in Supplemental Methods , including a list of antibodies in Supplemental Table 2 .…”

How to Slow down the Ticking Clock: Age-Associated Epigenetic Alterations and Related Interventions to Extend Life Span

“…An age-associated decrease in acetyl-CoA levels was suggested in the cortex of senescence-accelerated prone SAMP8 mice [75]. In addition, compared with 2 days old mice, 2 years old mice showed decreased acetyl-CoA signaling in cardiac stem cells [76]. Interestingly, acetyl-CoA synthesis was suggested to regulate lifespan in yeast [77].…”

“…Cells 2022, 11, x FOR PEER REVIEW 6 of 42 mice, 2 years old mice showed decreased acetyl-CoA signaling in cardiac stem cells [76]. Interestingly, acetyl-CoA synthesis was suggested to regulate lifespan in yeast [77].…”