Transcriptional Regulation in Epidermal Stem Cells

Contains fulltext : 203069.pdf (publisher's version ) (Open Access)Radboud University, 09 mei 2019Promotor : Veenstra, G.J.C. Co-promotor : Mulder, Klaas W.213 p

BLNCR is a long non-coding RNA adjacent to integrin beta-1 that is rapidly lost during epidermal progenitor cell differentiation

Contains fulltext : 200869.pdf (publisher's version ) (Open Access)10 p

Single-Cell ID-seq Reveals Dynamic BMP Pathway Activation Upstream of the MAF/MAFB-Program in Epidermal Differentiation

Contains fulltext : 198084.pdf (publisher's version ) (Open Access

Splicing and Chromatin Factors Jointly Regulate Epidermal Differentiation

Epidermal homeostasis requires balanced progenitor cell proliferation and loss of differentiated cells from the epidermal 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 jointly control genes involved in cell adhesion, a key process in epidermal maintenance. Using siRNA-based perturbation screens, we identified DNA and/or 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, and SMARCC2. ZMAT2 is an interactor of the pre-spliceosome that is required to keep cells in an undifferentiated, proliferative state. RNA immuno-precipitation and transcriptome-wide RNA splicing analysis showed that ZMAT2 associates with and regulates transcripts involved in cell adhesion in conjunction with ING5. Thus, joint control by splicing regulation, histone, and DNA modification is important to maintain epidermal cells in an undifferentiated state

Immuno-detection by sequencing enables large-scale high-dimensional phenotyping in cells

Contains fulltext : 193037.pdf (publisher's version ) (Open Access

Mutant p63 Affects Epidermal Cell Identity through Rewiring the Enhancer Landscape

Contains fulltext : 200262.pdf (publisher's version ) (Open Access)Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. Mutations in the p63 DNA-binding domain are associated with ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome. However, the underlying molecular mechanism of these mutations remains unclear. Here, we characterized the transcriptome and epigenome of p63 mutant keratinocytes derived from EEC patients. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity. Epigenomic analyses showed an altered enhancer landscape in p63 mutant keratinocytes contributed by loss of p63-bound active enhancers and unexpected gain of enhancers. The gained enhancers were frequently bound by deregulated transcription factors such as RUNX1. Reversing RUNX1 overexpression partially rescued deregulated gene expression and the altered enhancer landscape. Our findings identify a disease mechanism whereby mutant p63 rewires the enhancer landscape and affects epidermal cell identity, consolidating the pivotal role of p63 in controlling the enhancer landscape of epidermal keratinocytes