Increased Histone Acetylation and Decreased Expression of Specific Histone Deacetylases in Ultraviolet-Irradiated and Intrinsically Aged Human Skin In Vivo

Abstract

Histone deacetylases (HDACs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins and play a crucial role in epigenetic regulation. Previously, we showed that histone acetylation is implicated in ultraviolet (UV)-induced inflammation and matrix impairment. To elucidate the histone acetylation status and specific HDACs involved in skin aging, we examined the changes in histone acetylation, global HDAC activity, and the expression of HDACs and sirtuins (SIRTs) in intrinsically aged and photoaged human skin as well as in UV-irradiated human skin in vivo. Following acute UV irradiation, the acetylated histone H3 (AcH3) level was increased, but HDAC activity and the expression levels of HDAC4, HDAC11, and SIRT4 were significantly decreased. In intrinsically aged skin, AcH3 levels were increased, but HDAC activity and the expression levels of HDAC4, HDAC5, HDAC10, HDAC11, SIRT6, and SIRT7 were significantly decreased. However, histone acetylation and HDAC expression in photoaged skin were not significantly different from those in intrinsically aged skin. Collectively, HDAC4 and HDAC11 were decreased in both UV-irradiated and intrinsically aged skin, suggesting that they may play a universal role in increased histone acetylation associated with skin aging.

How good is the evidence that cellular senescence causes skin ageing?

“… Layer Sublayers Age-related changes Expected physiological and pathological consequences Epidermis General Decreased epidermal thickness May lead to changes in barrier function, such as increased water loss and susceptibility to infections ( Rorteau et al, 2020 ) Stratum corneum Altered lipid composition Changes in barrier function and skin dryness ( Starr et al, 2016 ) Stratum granulosum No significant difference in keratinocyte size, nuclear size or nuclear: cytoplasmic ratio ( Liao et al, 2013 ) – Stratum spinosum Apoptosis of keratinocytes ( Gilhar et al, 2004 ) May reflect reduced proliferative capacity, leading to reduced epidermal thickness ( Rübe et al, 2021 ) Stratum basale Reduced proliferative capacity of basal keratinocytes ( Rübe et al, 2021 ) Reduced height of basal keratinocytes ( Sauermann et al, 2002 ) Increased size of basal keratinocytes and nuclei ( Liao et al, 2013 ) Decreased number of melanocytes ( Gilchrest et al, 1979 ) Changes in the balance between differentiation and proliferation of basal keratinocytes, resulting in reduced maintenance of stratified layers ( Charruyer et al, 2021 , Rorteau et al, 2020 ) and an overall reduction in epidermal thickness ( Gilhar et al, 2004 ). Irregular skin pigmentation, both hyperpigmentation and hypopigmentation ( Lee et al, 2021a , Lee et al, 2021b , Lee, 2021 ) Dermo-epidermal junction – Reduced height of dermal papilla ( Sauermann et al, 2002 ) Reduced height of rete ridges and flattening of dermo-epidermal junction ( Newton et al, 2017 ) May lead to changes in skin barrier function (increased water loss and infection susceptibility) ( Rorteau et al, 2020 ), as well as reduced resistance to shearing ( Langton et al, 2019 ) Dermis Papillary Decreased quantity and thickness of collagen bundles ( …”

“…Shifts in histone chromatin marks, including markedly reduced levels of H4K16ac, absence of high H4K20me1 staining and increased cell-to-cell variability in total histone H3 and H4 content, are characteristic for ageing in the basal keratinocytes ( Dube et al, 2021 ) together with decreased expression of multiple histone deacetylases ( Lee, 2021 , Lee et al, 2021b , Lee et al, 2021a ). DNA methylation changes characteristically with age in human keratinocytes and fibroblasts, providing a basis for a skin cell-based methylation clock and, possibly, for the validation of anti-ageing interventions in skin ( Boroni et al, 2020 , Horvath et al, 2018 ).…”

“…In fact, cell senescence, especially senescence of dermal fibroblasts, has been postulated as a driver of skin ageing in many recent reviews ( Campisi et al, 2019 , Demaria et al, 2015 , Fitsiou et al, 2021 , Ho and Dreesen, 2021 , Lee, 2021 , Lee et al, 2021a , Lee et al, 2021b , Toutfaire et al, 2017 , Velarde and Demaria, 2016 , Wang and Dreesen, 2018 , Wlaschek et al, 2021 ). There is already good evidence for a causal role of cell senescence in photoaging of the skin, which has been covered in multiple recent reviews ( Cavinato and Jansen-Dürr, 2017 , Fitsiou et al, 2021 , Toutfaire et al, 2017 , Velarde and Demaria, 2016 ).…”

“…However, it has been shown that senescent fibroblasts can induce skin hyperpigmentation, which in turn might drive melanocyte senescence ( Yoon et al, 2018 ). Furthermore, stress-induced activation of p53 in keratinocytes drives paracrine induction of melanogenesis ( Murase et al, 2009 ), see also ( Lee, 2021 , Lee et al, 2021a , Lee et al, 2021b ) for review), which is associated with enhanced ROS production that might cause melanocyte senescence. At the present state of knowledge, it seems to be safe to assume that senescence in the epidermis (and possible in the complete skin) can arise in any of the main cell types and can be transmitted via paracrine bystander signaling to any other cell in the neighborhood.…”

“…It is well established that skin-resident immune cells respond to the chronic low-level inflammation associated with skin ageing ( Lee, 2021 , Lee et al, 2021a , Lee et al, 2021b ). However, to our knowledge, no information is available about whether these cells senesce and to what extent this may contribute to skin ageing.…”