Consistent with the rapid aging phenotype, HGPS cells undergo premature senescence in culture, providing an in vitro model for human aging. not form excess heterochromatin, the question remained whether or not proliferative arrest in this aging syndrome involved distinct epigenetic mechanisms. Here, we show that SADS provides a unifying event in both progeria and normal senescence. Additionally, SADS represents a novel, cytological-scale unfolding of chromatin, which is not concomitant with change to several canonical histone marks nor a result of DNA hypomethylation. Rather, SADS is likely mediated by changes to higher-order nuclear structural proteins, such as LaminB1. Introduction Cultured human primary cells have a limited life span and ultimately become incapable of further division despite remaining metabolically active. This irreversible exit from the cell cycle, widely referred to as cellular senescence, has important implications not only for aging and stem cell biology but also as a key anti-tumorigenesis mechanism. Senescence can be induced by a variety of mechanisms, including shortened telomeres (replicative senescence), oncogene expression, oxidative stress, and replicative exhaustion, or via expression of regulatory factors, such as the ubiquitin ligase SMURF2 (Zhang and Cohen, 2004; Zhang, 2007). Cellular senescence is usually accompanied by changes in gene expression and chromatin packaging; however, the absence of cell cycling is the only hallmark that consistently distinguishes senescent cells (Herbig et al., 2004; Cristofalo, 2005; Di Micco et al., 2011; Kosar et al., 2011). Formation of senescence-associated heterochromatic foci (SAHF) has received much attention, not only as a senescence marker but also as a proposed mechanism to promote and stabilize the senescent state (Narita et al., 2003; Zhang et al., 2007). Although SAHF exhibit repressive chromatin modifications, including H3K9Me3, H4 hypoacetylation, macroH2A, and HP1(Adams, 2007), some marks commonly associated with heterochromatin are lost during senescence and aging, such as linker histone H1 and DNA methylation (Funayama et al., 2006; Dimethylfraxetin Misteli, 2010). Although SAHF are common in human senescence, they are not found in all senescent human cells or any senescent mouse cells (Narita et al., 2003; Kennedy et al., 2010). In particular, cells from patients with Hutchinson Guilford progeria syndrome (HGPS) and from aged individuals tend to show loss of visible heterochromatin blocks Dimethylfraxetin and associated marks (Shumaker et al., 2006; Misteli, 2010). These inconsistencies leave open the question of whether or not cells in premature aging syndromes such as HGPS undergo the same process for loss of proliferative capacity as normal primary fibroblasts senescing in culture. Furthermore, even within normal cultured senescing fibroblasts it is not known whether SAHF are a key part of the senescence pathway or arise as a consequence of a senescent end state (Narita et al., 2003; Zhang et Dimethylfraxetin al., 2007; Kennedy et al., 2010; Di Micco et al., 2011). It would thus N10 be important to identify a broad epigenomic change to chromatin that consistently occurs during senescence in a variety of human and mouse systems and during premature arrest in cells from patients afflicted by HGPS. In contrast to the formation of excess facultative heterochromatin, constitutive heterochromatin in senescent cells has received little attention. Here, we demonstrate that this peri/centromeric satellite heterochromatin undergoes a striking decondensation in senescent cells. This dramatic change to structures key to cell division occurs consistently in a variety of senescence Dimethylfraxetin models, is not exclusive to either known senescent pathway, and happens independently of and before SAHF formation. It has Dimethylfraxetin also been observed in senescent human and mouse cells and appears to be prevalent in vivo in benign prostatic intraepithelial neoplasia (PIN) tumors. Importantly, this change to satellite heterochromatin is particularly prevalent in cultured fibroblasts from two HGPS patients. Thus, what we term senescence-associated distension of satellites (SADS) is usually a new marker that.