Epidermal differentiation gene regulatory networks controlled by MAF and MAFB

Abstract

Numerous regulatory factors in epidermal differentiation and their role in regulating different cell states have been identified in recent years. However, the genetic interactions between these regulators over the dynamic course of differentiation have not been studied. In this Extra-View article, we review recent work by Lopez-Pajares et al. that explores a new regulatory network in epidermal differentiation. They analyze the changing transcriptome throughout epidermal regeneration to identify 3 separate gene sets enriched in the progenitor, early and late differentiation states. Using expression module mapping, MAF along with MAFB, are identified as transcription factors essential for epidermal differentiation. Through double knock-down of MAF:MAFB using siRNA and CRISPR/Cas9-mediated knockout, epidermal differentiation was shown to be impaired both in-vitro and in-vivo, confirming MAF:MAFB's role to activate genes that drive differentiation. Lopez-Pajares and collaborators integrated 42 published regulator gene sets and the MAF:MAFB gene set into the dynamic differentiation gene expression landscape and found that lncRNAs TINCR and ANCR act as upstream regulators of MAF:MAFB. Furthermore, ChIP-seq analysis of MAF:MAFB identified key transcription factor genes linked to epidermal differentiation as downstream effectors. Combined, these findings illustrate a dynamically regulated network with MAF:MAFB as a crucial link for progenitor gene repression and differentiation gene activation.

Keywords: epidermal differentiation; epigenetics; lncRNA; regulatory network; stem cells; transcription factors.

Figure 1.

MAF:MAFB are central players in an epidermal differentiation regulatory network. In epidermal progenitors, lncRNA ANCR recruits EZH2 to suppress MAF/MAFB expression and enforce the progenitor state. During differentiation, p63 induces MAF/MAFB gene expression and lncRNA TINCR functions with STAU1 to stabilize MAF/MAFB transcripts. MAF/MAFB suppress the progenitor state and induce the expression of downstream transcription factors, ZNF750, KLF4, PRDM1 and GRHL3, in part by cooperating with p63, to promote epidermal differentiation.