Epigenetic regulation of epidermal differentiation

Abstract

In a cell, the chromatin state is controlled by the highly regulated interplay of epigenetic mechanisms ranging from DNA methylation and incorporation of different histone variants to posttranslational modification of histones and ATP-dependent chromatin remodeling. These changes alter the structure of the chromatin to either facilitate or restrict the access of transcription machinery to DNA. These epigenetic modifications function to exquisitely orchestrate the expression of different genes, and together constitute the epigenome of a cell. In the skin, different epigenetic regulators form a regulatory network that operates to guarantee skin stem cell maintenance while controlling differentiation to multiple skin structures. In this review, we will discuss recent findings on epigenetic mechanisms of skin control and their relationship to skin pathologies.

Figure 1.

DNA methylation. (A) DNA methyltransferases 3A and 3B (DNMT3A/B) catalyze the de novo addition of a methyl group to cytosine in the CpG context. (B) After cell division, DNMT1 is responsible for copying the DNA methylation pattern from the mother strand to the daughter strand to maintain the DNA methylation pattern. This process is aided by UHRF, which binds hemimethylated CpG sequences. (C) The presence of methyl groups in the DNA can block the binding of transcriptions factors or be recognized by other methyl-binding proteins as MeCP2 or MBD that recruit other chromatin repressors (e.g., histone deacetylases [HDACs]), resulting in chromatin condensation and silencing of gene expression. See main text for details.

Figure 2.

Chromatin remodeling and histone code. (A) Inside the nucleolus, ∼146 bp of DNA are wrapped around the nucleosome core, an octamer protein complex composed of four histone heterodimers: two H2A-H2B and two H3-H4. Between protein octamers, histone H1 helps to stabilize the linker DNA. The amino terminus of each core histone protrudes outside the protein octamer. These “histone tails” are the target of posttranslational modifications. Histone tail modifications described in the text are presented in (B). The histone acetyltransferases (HATs) catalyze the addition of acetyl residues on specific lysine residues. Other conserved lysine residues are methylated. In particular, the activity of the polycomb repressive complex 2 (PRC2; through the enzymatic activity of Ezh1 and Ezh2) mediates the di- and trimethylation of the Lysine 27 on the Histone H3. This modification is then recognized by the PRC1 mediating the condensation and epigenetic silencing of a DNA region. See main text for details. The lysine residue modified by the methyltransferase activity of Setd8 is also represented. (C) Under some circumstances, histone variants are introduced into the nucleosome by histone chaperones. See main text for details. (D) Nucleosome positioning can be altered by ATP-dependent chromatin-remodeling complexes that results in a more relaxed chromatin permissive for transcription.

Figure 3.

Effects of epigenetic regulation on skin stem cells. Different epigenetic mediators operate to repress multiple effector genes to maintain stem cell proliferation and differentiation in (A) the hair follicle, and (B,C) the interfollicular epidermis. See main text for details.