Heterochromatin loss

Heterochromatin is the condensed, transcriptionally repressed fraction of chromatin marked by histone modifications such as H3K9me2/3 and H3K27me3, and maintained by factors including HP1 proteins, the polycomb repressive complexes and DNA methylation; it silences repetitive elements, maintains genome stability and enforces cell-type-specific gene expression patterns. With age, heterochromatin — particularly constitutive heterochromatin at pericentromeric and telomeric regions — undergoes progressive loss and spatial reorganisation, a process associated with de-repression of retrotransposons, ectopic gene expression and genomic instability. Lamin A dysfunction, HDAC sirtuin decline and the epigenetic drift captured by DNA methylation clocks all converge mechanistically on heterochromatin erosion, making it a proposed upstream driver linking multiple hallmarks of ageing.