ΔNp63α-mediated epigenetic regulation in keratinocyte senescence.

EPIGENETICS 2023, VOL. 18, NO. 1, 2173931 https://doi.org/10.1080/15592294.2023.2173931 REVIEW ΔNp63α-mediated epigenetic regulation in keratinocyte senescence Linghan Kuanga,b and Chenghua Li c a Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China; bKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China; cCenter of Growth, Metabolism and Aging, Key Laboratory of Biological Resources and Ecological Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China ABSTRACT Keratinocyte senescence contributes to skin ageing and epidermal dysfunction. According to the existing knowledge, the transcription factor ΔNp63α plays pivotal roles in differentiation and proliferation of keratinocytes. It is traditionally accepted that ΔNp63α exerts its functions via binding to promoter regions to activate or repress gene transcription. However, accumulating evidence demonstrates that ΔNp63α can bind to elements away from promoter regions of its target genes, mediating epigenetic regulation. On the other hand, several epigenetic alterations, including DNA methylation, histone modification and variation, chromatin remodelling, as well as enhancer-promoter looping, are found to be related to cell senescence. To systematically elucidate how ΔNp63α affects keratinocyte senescence via epigenetic regulation, we comprehensively compiled the literatures on the roles of ΔNp63α in keratinocyte senescence, epigenetics in cellular senescence, and the relation between ΔNp63αmediated epigenetic regulation and keratinocyte senescence. Based on the published data, we conclude that ΔNp63α mediates epigenetic regulation via multiple mechanisms: recruiting epigenetic enzymes to modify DNA or histones, coordinating chromatin remodelling complexes (CRCs) or regulating their expression, and mediating enhancer-promoter looping. Consequently, the expression of genes related to cell cycle is modulated, and proliferation of keratinocytes and renewal of stem cells are maintained, by ΔNp63α. During skin inflammaging, the decline of ΔNp63α may lead to epigenetic dysregulation, resultantly deteriorating keratinocyte senescence. Introduction The largest organ of the human body, skin, acts as a protective barrier on our surface. It is also responsible for maintaining homoeostasis of var ious substances as well as sensory perception and temperature regulation [1,2]. Keratinocyte is the predominant cell type in the epidermis, which is the outermost layer of the skin. Senescence of keratinocytes is an important part of skin ageing, which may impair the functions of skin. Numerous studies show that epigenetic alterations are involved in skin ageing and cell senescence [3– 5]. p53 family proteins are key transcription fac tors controlling cell cycle [6]. p63 belongs to p53 gene family and encodes multiple protein iso forms, among which ΔNp63α is the predominant species expressed in the skin tissue [7]. As a key transcription factor in keratinocyte differentiation and renewal, ΔNp63α plays key roles to maintain ARTICLE HISTORY Received 12 September 2022 Revised 26 December 2022 Accepted 12 January 2023 KEYWORDS Keratinocyte; skin aging; cellular senescence; cell proliferation; ΔNp63α; epigenetic regulation; chromatin remodeling proliferation of keratinocytes and to prevent them from undergoing senescence. It is traditionally accepted that ΔNp63α exerts proliferative func tions via binding to promoter regions of various cell cycle arresting genes (e.g., Pten, p16INK4a and p21WAF1/CIP1) and consequently downregulating their expression [7–9]. Recently, ΔNp63α has been found to act as a pioneer transcription factor to regulate gene expression via binding to regions other than promoters [10,11]. In this review, we focus on the epigenetic regulation of ΔNp63α in preventing keratinocyte senescence. ΔNp63α and senescence of keratinocytes The skin consists of three layers, the epidermis, der mis, and hypodermis, each of which is separate but functionally interdependent. The outermost layer, epi dermis, is predominantly composed of keratinocytes, which provide hardness and moisture-lock properties CONTACT Chenghua Li Center of Growth, Metabolism and Aging, Key Laboratory of Biological Resources and Ecological Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 2 L. KUANG AND C. LI to the skin [1]. Keratinocytes are continuously prolif erating to renew the outer skin barrier. They migrate upwards and differentiate into cells that comprise the epidermis [12–14]. Skin undergoes intrinsic or chronological age ing, as a consequence of internal and external changes due to passage of time [15]. Owing to extensive contact with the outside environment, epidermal tissues (especially keratinocytes) are continuously exposed to diverse external stimuli, which can cause inflammaging [16–18]. Alongside inflammaging of the skin, the chronic low-level pro-inflammatory cytokines, in concert with the external stimuli, may induce and deteriorate senes cence of keratinocytes and other skin-resident stromal cells. As a continuously renewing epithe lium, the epidermis relies heavily on the prolifera tive potential of keratinocytes to work as a functional barrier of our body [19]. Senescence of keratinocytes may lead to decline of their phy siological functionality, which accelerates the age ing process of skin tissues [13,20]. In particular, these senescent keratinocytes produce a complex secretome, which is termed senescence-associated secretory phenotype (SASP) and leads to some detrimental effects, such as paracrine senescence, immune evasion, inflammation, and tumorigenesis (depicted as Figure 1a) [21]. As an indispensable transcription factor in ker atinocytes, ΔNp63α plays a master role in main taining proliferation and preventing senescence of these cells [19]. ΔNp63α is encoded by p63 gene, which belongs to the p53 transcription factor gene family and produces multiple protein isoforms [7,22]. Among them, ΔNp63α is the predominant isoform in somatic cells, especially in keratinocytes [23–25]. As depicted in Figure 2a, ΔNp63α directly binds to p63-responsive elements (p63REs) in pro moter regions of its target genes to mediate either transcriptional activation or inhibition in different scenarios [7,26]. These p63REs can also be recog nized by other p53 family members, including p53, TAp63 and p73 proteins. Competitive associati (...truncated)