The Histone Code of Senescence

Abstract

Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the adaptation of the cells to an unfavorable, demanding and stressful microenvironment. This adaptation is orchestrated through a deep epigenetic resetting. A first wave of epigenetic changes builds a dam on irreparable DNA damage and sustains the pro-survival response and the cell-cycle arrest. Later on, a second wave of epigenetic modifications allows the genomic reorganization to sustain the transcription of pro-inflammatory genes. The balanced epigenetic dynamism of senescent cells influences physiological processes, such as differentiation, embryogenesis and aging, while its alteration leads to cancer, neurodegeneration and premature aging. Here we provide an overview of the most relevant histone modifications, which characterize senescence, aging and the activation of a prolonged DNA damage response.

Histone methyltransferase Smyd3 is a new regulator for vascular senescence

“…This array of histone modifications orchestrates to regulate various biological processes including aging and senescence. Imbalance of activating and repressive histone modifications has been reported to occur in senescence (Paluvai, Di Giorgio, & Brancolini, 2020). Histone modifications can be under the complex regulation of variety of modifications, including histone methylation and histone acetylation (Wang, Yuan, & Xie, 2018).…”

Quis Custodiet Ipsos Custodes (Who Controls the Controllers)? Two Decades of Studies on HDAC9

“…These results are in agreement with a previous report about the increased immunosuppressive properties of Hdac9 -/- Tregs [ 78 ]. Most of these properties are due to the Hdac9-dependent inhibition of Mef2d, that in Tregs allows the acquisition of an effector Treg phenotype [ 107 , 108 ].…”

Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword

“…Epigenetic alterations are vital for the senescence-associated DDR and p16 expression. However, epigenetic mechanisms that control senescence go much further [ 44 ]. For instance, the H3K9me3 histone modification is fundamental, and changes in the activity or levels of the enzymes associated with the deposition or removal of the methylation (methyltransferases or demethylases, respectively) can induce or reverse senescence [ 45 , 46 , 47 ].…”

“…For instance, the H3K9me3 histone modification is fundamental, and changes in the activity or levels of the enzymes associated with the deposition or removal of the methylation (methyltransferases or demethylases, respectively) can induce or reverse senescence [ 45 , 46 , 47 ]. Similarly, redistribution of histone variants is a senescence mechanism to control gene expression [ 44 ]. In particular, incorporation of histone variant H3.3 drives cell cycle arrest by downregulating proliferation-promoting genes [ 48 ], whereas, H2A.J and macroH2A1 promote the SASP [ 49 , 50 ].…”