RBM28: Funktionsanalyse, Krankheitsrelevanz und Rolle in der neuroepithelialen Gewebeentwicklung
Zusammenfassung der Projektergebnisse
Alopecia-Neurological defects-Endocrinopathy (ANE) syndrome is a rare inherited hair disorder, which had been shown to result from decreased expression of the RNA binding motif protein 28 (RBM28). In our collaborative research program we focussed on the role played by RBM28 in the pathogenesis of ANE, combining our expertises in human molecular genetics (Sprecher / Kanaan), cell biology and mouse genetics (Gat), and RNA biochemistry (Bindereif). First, we obtained evidence for the direct involvement of RBM28 in hair growth. When RBM28 was down-regulated in human hair follicle (HF) organ cultures, we observed catagen induction and HF growth arrest, indicating that RBM28 is necessary for normal hair growth. We also aimed at identifying molecular targets of RBM28: Based on a global correlative study of mRNA and miRNA expression profiles in RBM28 knock-down cells, we found that RBM28 controls the expression of miR-203. miR-203 regulates in turn TP63, encoding the transcription factor p63, which is critical for hair morphogenesis. Second, we applied the iCLIP-Seq approach (individual crosslinkingimmunoprecipitation, combined with RNA-Seq) to identify global RNA targets of RBM28 in HEK293 cell culture. As expected from the nucleolar localization of RBM28 and the putative homology to the yeast rRNA processing factor Nop4, we found a multitude of RNA contacts in the ribosomal RNA (rRNA) and/or rRNA modification machinery, such as snoRNAs. However, we were unable to detect any significant change in RNA modification, as far as this could be analyzed (pseudouridylation pattern of human U5 snRNA). We have to conclude that at least in this specific case of an snRNA modification, affecting human U5 snRNA, RBM28 appears not to play an essential role.
Projektbezogene Publikationen (Auswahl)
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RBM28, a protein deficient in ANE syndrome, regulates hair follicle growth via miR-203 and p63. Exp Dermatol. 2015 Aug;24(8):618-22
Emily Warshauer, Liat Samuelov, Ofer Sarig, Albrecht Bindereif, Moien Kanaan, Uri Gat, Dana Fuchs-Telem, Noam Shomron, Luba Farberov, Metsada Pasmanik-Chor, Gil Nardini, Eyal Winkler, Benjamin Meilik, Isabelle Petit, Daniel Aberdam, Ralf Paus, Eli Spreche
