AP-1 Imprints a Reversible Transcriptional Program of Senescent Cells

Abstract

Senescent cells play important physiological-and pathophysiological roles in tumor suppression, tissue regeneration, and aging. While select genetic and epigenetic elements crucial for senescence induction were identified, the dynamics, underlying epigenetic mechanisms, and regulatory networks defining senescence competence, induction and maintenance remain poorly understood, precluding a deliberate therapeutic manipulation of these dynamic processes. Here, we show, using dynamic analyses of transcriptome and epigenome profiles, that the epigenetic state of enhancers predetermines their sequential activation during senescence. We demonstrate that activator protein 1 (AP-1) 'imprints' the senescence enhancer landscape effectively regulating transcriptional activities pertinent to the timely execution of the senescence program. We define and validate a hierarchical transcription factor (TF) network model and demonstrate its effectiveness for the design of senescence reprogramming experiments. Together, our findings define the dynamic nature and organizational principles of gene-regulatory elements driving the senescence program and reveal promising inroads for therapeutic manipulation of senescent cells.

LSEC model of aging

“…It is not fully understood how enhancer chromatin, epigenetic marks, transcription factor recruitment, and the organizational principles of transcription factor networks drive the senescence program. Recent studies showed that the senescence program is predominantly encoded at the enhancer level [66,67] and that the enhancer landscape is dynamically reshaped at each step of the senescence transition [68]. A deeper understanding of the underlying mechanisms might help identify ways in which enhancer regulation could be manipulated to overcome potential SR and endocytosis gene transcriptional silencing in senescent LSECs, which express enhanced levels of heterochromatic marks such as macroH2A and Histone H9Me2 [39].…”

“…This approach represents a broader direction that is not restricted just to reversing transcriptional silencing of SRs but to changes of entire transcriptional network to a younger nonsenescent state. Pioneer transcription factors (that directly bind condensed chromatin) are critical in establishing new cell fate competence: they grant longterm chromatin access to non-pioneer factors and help determine cell identity by opening and licensing the enhancer landscape [68,70,71]. In addition, DNA methylation could play an important role in establishment of senescence as recently was shown for a DNMT1dependent downregulation of BRCA1/ZNF350/RBBP8 repressor complex in the course of oncogene-induced senescence [72].…”

A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence

“…In this study, we pioneered the use of interspecies genetic divergence to screen for components of the senescence regulatory machinery. This strategy complements previous studies of transcription factor binding sites in genes of the senescence program in a single genetic background (17,21). Our approach harnesses the correlation between interspecies variation in sequence and expression levels, as an additional line of evidence for senescence-specific regulatory functions by a given factor.…”

“…However, given the complexity of the senescence program, many more regulators likely remain to be identified. Indeed, bioinformatic approaches have identified dozens of other transcription factor candidates in senescence (17)(18)(19)(20)(21)(22)(23)(24), many of which remain unvalidated (but see (18)(19)(20)(21) for recent discoveries of the roles of DLX2, FOXO3 and AP-1 in senescence).…”

Conclusive Identification of Senescent T Cells Reveals Their Abundance in Aging Humans

“…3B). Functional overrepresentation profiling enriched for a highly diverse array of biological processes consistent with a senescence response in the yellow module, including 'p53 pathway, 'Inflammatory response', and 'TGFß signaling', many which overlapped with pathways also activated in senescent human fibroblasts (24,25) (Fig. S4E-F).…”