Cell-nonautonomous effects of lysosphingolipids on the genomic and epigenomic stability of human cardiomyocytes: implications for cellular and tissue ageing

• Applicant: Professor Leo Kurian, Ph.D.
• Subject Area: Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 452934302

Cardiac function dramatically declines with age. We recently uncovered a new, unforeseen, and evolutionarily-conserved contributor to this decline in the accumulation of the lysosphingolipid sphinganine (DHS). The DHS-derivative, sphinganine-1-phosphate (DHS1P), directly inhibits HDACs causing aberrant hyperacetylation of histone tails and transcriptional activation. These effects give rise to widespread DNA damage, which in turn is concomitant with the impairment of various cardiac functions tested both in vitro and in vivo. Despite the importance of these findings, and the recorded cardiac-specific accumulation of DHS, the mechanistic and molecular details of this metabolism-to-genome instability axis remain vague. Thus, we propose here that DHS accumulation in the human heart underlies changes in chromatin accessibility and resilience towards DNA damage lesions, while also affecting transcriptional fidelity. In response to this, we have designed a research plan to (i) measure DHS-relevant metabolites in the serum of age- and disease-stratified human cohorts to explore their prognostic potency; (ii) perform targeted loss-of-function screens to identify the enzymatic and metabolic activities linked to DHS-induced genomic instability in human cardiomyocytes; (iii) apply state-of-the-art genomics to map the genomic hotspots of transcriptional hyperactivation and DNA damage targeting in respect to chromosomal compartments; (iv) obtain a single-cell and temporally-resolved understanding of the genomic response to DHS accumulation. Once integrated, these approaches are bound to offer a new understanding of how lysophingolipid levels mount and cause DNA damage specifically in the heart and, thus, point to druggable targets for alleviating age-associated cardiac dysfunction.

• DFG Programme: Research Grants