MLL, TERRA, and telomere chromatin dynamics in replicative senescence and aging.

Abstract

Replicative senescence links telomere shortening to irreversible proliferative arrest and is widely recognized as a major tumor-suppressive mechanism. At the organismal level, however, progressive accumulation of senescent cells contributes to tissue dysfunction, chronic inflammation, and aging. Accumulating evidence suggests that telomere shortening influences telomeric and subtelomeric chromatin organization and transcription through mechanisms that remain incompletely understood. Building upon the telomere position effect model of cellular senescence and the subtelomere-telomere theory of aging, this review proposes a chromatin-sensing telomere theory of aging in which telomere shortening contributes to senescence through epigenetic and transcriptional changes at chromosome ends. Central to this model is TERRA, a long non-coding RNA that regulates telomeric chromatin structure, telomere maintenance, and DNA-damage responses. The lysine methyltransferase MLL/KMT2A is a key regulator of TERRA transcription. MLL associates with telomeric chromatin in a telomere length-dependent manner and promotes TERRA transcription through H3K4 methylation. Shelterin components, particularly TRF2, can repress TERRA transcription in certain experimental contexts, and we propose that telomere shortening progressively remodels the shelterin-dependent telomere-subtelomere chromatin environment, potentially reducing access of MLL and RNA polymerase II to subtelomeric promoters. A biphasic model of TERRA regulation is proposed in which early TERRA upregulation in aging tissues promotes telomere protection, while subsequent critical shortening of TERRA-dominant telomeres contributes to reduced TERRA expression, telomere dysfunction, and senescence. This theory proposes a mechanistic link between telomere shortening, chromatin regulation, and quasi-programmed aging.