Investigating the role of histone deacetylases in epidermal ageing

Abstract

In skin, keratinocytes (KCs) constitute around 95% of the epidermis and are vital for its structural integrity and barrier function. With ageing, there is a decline in KC function, which is further exacerbated by exposure to environmental factors, particularly solar ultraviolet radiation (UVR). Topical application of all-trans retinoic acid (ATRA) is shown to elicit skin rejuvenation in part through stimulation of KC turnover, making it the clinical “gold standard� treatment for aged skin. Histone deacetylases (HDACs) are epigenetic enzymes whose alteration in either expression or activity modulates chromatin structure and cell cycle progression. To date, the role of HDACs play in human epidermal ageing remains unclear. Therefore, this thesis aimed to: i) determine a robust in vitro KC system for the study of HDAC expression during KC ageing by comparing an immortalised cell line, HaCaT, to primary normal human epidermal keratinocytes (NHEKs) obtained from juvenile (1-6 y/o), middle-aged (47-61 y/o) and aged donors (80-85 y/o); ii) investigate the influence of environmental stressors on HDAC expression and activity to assess whether this impacts KC ageing; and, iii) examine whether ATRA impacts HDAC expression and hence contributes to rejuvenation. Western blot analyses identified that HaCaTs did not recapitulate the HDAC expression profiles observed in NHEKs, and that NHEK expression of HDACs were age-dependent. HaCaTs exhibited higher HDAC activity than both juvenile and aged NHEKs (P

Date of Award	1 Aug 2025
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Rachel Watson (Supervisor) & Abigail Langton (Supervisor)