Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging

Epigenetic regulation of aging: implications for interventions of aging and diseases

“… 80 Additionally, diminished levels of H3K9me3 and HP1 were identified in mesenchymal stem cells (MSCs) bearing pathogenic mutations of HGPS or Werner Syndrome (WS), another human disease with accelerated aging. 81 – 83 The expression of the H3K9me3 methyltransferase SUV39H1 is decreased during the aging of both human and mouse HSCs, 84 leading to a global reduction in H3K9 trimethylation and perturbed heterochromatin function. 84 Treatment of Werner syndrome (WS)-specific MSCs with vitamin C, gallic acid (GA), or low-dose chloroquine (CQ) ameliorates a range of senescent phenotypes, promotes cell self-renewal, and upregulates levels of heterochromatin-associated marks, including H3K9me3.…”

“…Significant chromatin structural remodeling has been identified during cellular senescence, from histone component and modification changes to alterations of the chromatin compartments and topologically associating domains (TADs). 83 , 116 , 117 Global canonical histone loss is regarded as a common feature of aging from yeast to humans. 108 , 118 , 119 Overexpression of histone H3/H4 in yeast extends the lifespan, suggesting that an increased pool of free histones promotes survival during aging by facilitating nucleosome exchange and post-transcriptional chromatin repackaging.…”

“… 138 The disruption of higher-order chromatin structure and the separation of heterochromatin from the nuclear membrane are observed during cellular senescence and aging. 63 , 83 , 130 , 139 – 141 A hierarchy of integrated structural state changes has been characterized through large-scale epigenomic analyses of isogenic young, senescent, and progeroid hMPCs, manifested as heterochromatin loss in repressive compartments, euchromatin weakening in active compartments, switching in interfacing topological compartments, and increasing epigenetic entropy. Nuclear lamina dysfunction results in the derepression of constitutive heterochromatic regions in repressive LAD structures marked by H3K9 methylations.…”

The landscape of aging

“…Additionally, SIRT6 deficiency is closely associated with progeroid phenotypes (Korotkov et al, 2021), and SIRT7 safeguards the chromatin architecture to control innate immune signaling during stem cell aging (Bi et al, 2020). Apart from linear histone post-translational modifications, the large-scale radial repositioning of chromatin structure at each hierarchical layer also converges to significantly progress of aging (Janssen and Lorincz, 2022;Liu et al, 2022b;Liu et al, 2022c). Nuclear deformation, in part due to the diminished core components of nuclear lamina meshworks (i.e., Lamin B1 and LAP2) and heterochromatin proteins (i.e., HP1), is associated with the detachment of periphery heterochromatin (also known as lamina-associated domains [LADs]) from nuclear lamina, resulting in heterochromatin erosion and instability (Deng et al, 2021;Liang et al, 2021).…”

“…The heterochromatin also becomes globally derepressed and more accessible in senescent cells, demonstrated by the loss of constitutive histone modifications (H3K9me3 and H4K20me3) and increased chromatin accessibility . The relaxed chromatin state segregates from the leakage expression of developmentally restricted genes (e.g., placenta-specific genes [PSGs]), as well as repetitive elements that are originally sealed in LADs (e.g., HERV and LINE1 elements) (De Cecco et al, 2013a;Deng et al, 2019;Liu et al, 2021e;Liu et al, 2022c;Liu et al, 2022d;Peng and Karpen, 2007). Although these elements are typically silenced in young cells, their derepression can trigger an IFN-I response and sterile inflammation, causally linked to cellular senescence, such as in human mesodermal cells (Bi et al, 2020;De Cecco et al, 2019).…”