Sunday, May 11, 2025
5/11/2025
Cytosolic DNA is the Link Between Genomic Instability and Cardiovascular Aging - Premature aging syndromes in laminopathies caused by mutations in the LMNA gene, encoding nuclear envelope protein lamin A/C (LMNA), are the prototypic examples of genomic instability, which is a hallmark of “normal” aging. Cardiovascular involvement is the cardinal phenotype and the major cause of mortality and morbidity. The pathogenesis of laminopathies and “normal” aging share several common mechanisms. LMNA regulates mitochondrial function, telomere length, nutrient sensing, stem cell regeneration, and autophagy, which are the classic hallmarks of “normal aging”. LMNA expression is reduced in “normal” aging. A similar set of nuclear defects are observed in “normal” aging and laminopathies. LMNA also regulates several epigenetic regulators of aging, including sirtuins and histone deacetylases. Furthermore, LMNA is essential for genomic instability and induction and repair of the double-stranded DNA breaks (DSBs) as well as the mechanical integrity of the nuclear membrane. These mechanisms are also the core mechanisms of “normal” aging. We have shown that the cytosolic DNA (CyDNA)-sensing proteins CGAS/STING1 are induced and their downstream effectors TBK1, IRF3, and NFKB are activated, and the senescence-associated secretory phenotype (SASP) is expressed in the human hearts and mouse models of laminopathies. We also have identified and defined the LMNA-associated domains (LADs) in human cardiac myocytes (CMs) and have shown that LADs are shifted in laminopathies and regulate CpG methylation and gene expression. Moreover, we have identified 711 DSBs (q<0.05) in the nDNA in the LMNA-deficient as compared to the wild-type (WT) CMs by END-Sequencing (END-Seq). DSBs show a preponderance toward the protein-coding genes, which is consistent with the role of the LMNA in defining the boundaries of TADs and TOP2B processing. Furthermore, we have shown that deletion of the Mb21l1 gene, encoding CGAS, attenuates the phenotype in a mouse model of cardiac laminopathies. Therefore, we logic that studying premature aging in laminopathies would provide insights into the mechanisms that are shared with “normal” aging. The large effect sizes of the LMNA mutations would provide a better resolution in discerning the deranged hallmarks of aging than the “normal” aging, whereby numerous determinants, each with a small effect size, interact stochastically to induce aging. Thus, we propose to identify and characterize the genome-wide DSBs in CMs, cardiac fibroblasts (CFs), and endothelial cells (ECs) in laminopathies and the old WT mice by END-Seq, the former because of the involvement of multiple cell types in laminopathies and the latter to assess the extension of the findings in laminopathies to “normal” aging. Likewise, we propose to identify and characterize the sources of the CyDNA in CMs, CFs, and ECs in laminopathies by CGAS ChIP-Seq. Moreover, we propose to determine the effects of genetic blockade of the STING1 on selected hallmarks of aging and cardiac phenotype in laminopathies. The findings are expected to provide insights into the molecular basis of premature CV aging in laminopathies and likely the hallmarks of “normal” aging.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).