Remodeling of three-dimensional genome architecture in cardiac development and aging.

Abstract

We used the Tibetan pig, a miniature swine breed, as a human heart model. By investigating the alterations in higher-order chromatin structure and transcriptional regulation spanning from the fetal stage to sexual maturity and early senescence, we aimed to elucidate their functions in physiological development and the aging process. To assess the Tibetan pig's suitability as a biomedical model and a potential organ donor for humans, we conducted cross-species comparisons of transcriptomes and chromatin structures between human and porcine hearts.Our study uncovered several previously unreported phenomena regarding structural changes in the three-dimensional genome across multiple scales. Changes in intensity of B-B interactions and correlation between sequence features and A/B compartment switches revealed that heterochromatin gradually stacked and relaxed during development and senescence. A finer examination of TADs and loops/PEIs showed that, compared to fetal and aged pigs, young adults boast higher correlation of gene expression and TAD connectivity, more space between dynamic boundaries and their targeted genes, and stronger 'loop skew' towards A compartments, indicating that young adults tend to have finer control of chromatin structure dynamics than fetal and aged pigs.Cross-species analyses of human-specific gene expression and chromatin structure changes compared to pigs indicated stronger cardiac contractility in humans, providing insights into evolution and physiological incompatibility of pig-to-human heart xenotransplantation. In particular, we found that human-specific loops showed motif enrichment of TFs TEAD1, TBX20 and ZEB2, whose target genes were mainly over-represented in cardiac contraction and fatty acid metabolism. In addition, we also observed human-specific elevated gene expression for TRPM1 and STIM, which reside in proximity to human-specific TAD boundaries and are known to play critical roles in calcium and potassium transmembrane transport.