Nucleolar buffering of lamina-associated heterochromatin restrains Progerin-induced ageing programs

Abstract

Nucleolar enlargement is a conserved hallmark of physiological and premature ageing, including Hutchinson-Gilford Progeria Syndrome (HGPS), a disorder caused by LMNA mutations that produce Progerin and profoundly disrupt nuclear architecture. Although both the nuclear lamina and nucleolus organize repressive chromatin, how nucleolar remodelling contributes to genome reorganization during ageing driven by lamina dysfunction remains unclear. Here, we identify the nucleolus as a stress-responsive chromatin-organizing compartment that buffers the initial events of Progerin-induced ageing programs by sequestering lamina-associated domains (LADs). Despite widespread nuclear reorganization and robust transcriptional ageing signatures following Progerin expression, repression of LADs is preserved. This preservation results from an increased nucleolar association of lamina-released LADs, which can retain H3K9me2 and remain transcriptionally silent. Disrupting this compensatory pathway by depleting NPM1, a nucleolar factor required for nucleolar genome association, abolishes nucleolar buffering, leading to loss of H3K9me2 at relocated LADs, derepression of LAD-associated genes, exacerbation of transcriptional ageing programs, and increased DNA damage. Together, these findings establish the nucleolus as a structural fail-safe that preserves heterochromatin integrity and reveal stress-responsive nuclear compartmentalization as a fundamental mechanism safeguarding epigenome stability.