Splicing and epigenetic factors jointly regulate epidermal differentiation

Abstract

Highlights-Gene-perturbation screens identify a role for ZMAT2 in the control of human epidermal differentiation. -ZMAT2 functionally interacts with known epigenetic regulators of epidermal differentiation. -ZMAT2 interacts with the pre-spliceosome and transcripts involved in cell adhesion. -ZMAT2 mediated splicing and epigenetic control jointly target an adhesion related transcriptional program in human epidermal stem cells. AbstractEpidermal homeostasis requires a continuous balance between progenitor cell proliferation and loss of differentiated cells from its surface. During this process cells undergo major changes in their transcriptional programs to accommodate new cellular functions. We found that transcriptional and post-transcriptional mechanisms underlying these changes are functionally connected and jointly control genes involved in cell adhesion, a key process in epidermal maintenance. Using siRNA-based perturbation screens, we identified novel DNA/RNA binding regulators of epidermal differentiation. Computational modeling and experimental validation identified functional interactions between the matrin-type 2 zinc-finger protein ZMAT2 and the epigenetic modifiers ING5, SMARCA5, BRD1, UHRF1, BPTF, SMARCC2. ZMAT2 is required to keep cells in an undifferentiated, proliferative state and quantitative proteomics identified ZMAT2 as an interactor of the pre-spliceosome. RNA-Immunoprecipitation and transcriptome-wide RNA splicing analysis showed that ZMAT2 associates with and regulates transcripts involved in cell adhesion in conjuction with ING5. Thus, joint control by post-transcriptional and epigenetic mechanisms is important to maintain epidermal cells in an undifferentiated state.