2A-DUB/Mysm1 Regulates Epidermal Development in Part by Suppressing p53-Mediated Programs.

Christina Wilms,Maximilian Wagner,Adelheid Hainzl,Marius Alupei,Titus Brinker,Ioanna Krikki,Sonja Kilo,Evgenia Makrantonaki,Martina Gatzka,Carsten Kroeger

doi:10.3390/ijms19030687

Abstract

Development and homeostasis of the epidermis are governed by a complex network of sequence-specific transcription factors and epigenetic modifiers cooperatively regulating the subtle balance of progenitor cell self-renewal and terminal differentiation. To investigate the role of histone H2A deubiquitinase 2A-DUB/Mysm1 in the skin, we systematically analyzed expression, developmental functions, and potential interactions of this epigenetic regulator using Mysm1-deficient mice and skin-derived epidermal cells. Morphologically, skin of newborn and young adult Mysm1-deficient mice was atrophic with reduced thickness and cellularity of epidermis, dermis, and subcutis, in context with altered barrier function. Skin atrophy correlated with reduced proliferation rates in Mysm1−/− epidermis and hair follicles, and increased apoptosis compared with wild-type controls, along with increases in DNA-damage marker γH2AX. In accordance with diminished α6-Integrinhigh+CD34+ epidermal stem cells, reduced colony formation of Mysm1−/− epidermal progenitors was detectable in vitro. On the molecular level, we identified p53 as potential mediator of the defective Mysm1-deficient epidermal compartment, resulting in increased pro-apoptotic and anti-proliferative gene expression. In Mysm1−/−p53−/− double-deficient mice, significant recovery of skin atrophy was observed. Functional properties of Mysm1−/− developing epidermis were assessed by quantifying the transepidermal water loss. In summary, this investigation uncovers a role for 2A-DUB/Mysm1 in suppression of p53-mediated inhibitory programs during epidermal development.

Highlights

Tissues with high cell turnover, such as the hematopoietic system, the skin, and the intestines, require an elaborate cooperation of chromatin-remodeling and histone-modifying enzymes with sequence-specific transcription factors (TF) and tumor suppressor (TS) genes, to orchestrate the coordinated differentiation and maintenance of stem cells (SC), and to ensure the life-long supply with functional cells [1]
Mysm1 Expression in Murine Skin Declines with Age
In accordance with a potential role of Mysm1 in skin development, Mysm1 protein expression was highest in newborn mice (p1–3) (Figure 1A)—with successive decline upon aging (Figure 1A–D)

Summary

Introduction

Tissues with high cell turnover, such as the hematopoietic system, the skin, and the intestines, require an elaborate cooperation of chromatin-remodeling and histone-modifying enzymes with sequence-specific transcription factors (TF) and tumor suppressor (TS) genes, to orchestrate the coordinated differentiation and maintenance of stem cells (SC), and to ensure the life-long supply with functional cells [1]. The transcriptional balance of the “epidermal differentiation complex” (EDC), encoding for genes involved in epidermal maturation, such as loricrin, involucrin, and filaggrin, vs epithelial stemness genes, is determined by an intricate interplay of general ATP-dependent chromatin-remodeling enzymes (including Brg, Satb, Mi-2β), DNA methyl transferases (Dnmt1), polycomb group (PcG) factors, and histone deacetylases (Hdac1/2), that collaborate with epithelia-related master TF, such as p63, Klf, Sox, and others (reviewed in [5,6,7,8]). The exact mechanisms of the interactions between different epigenetic factors and modifications and sequence-specific TF at different stages of epidermal development and homeostasis are still only incompletely understood

Methods

Results

Conclusion