ZNF354C is a transcriptional repressor that inhibits endothelial angiogenic sprouting

  • Zinc finger proteins (ZNF) are a large group of transcription factors with diverse functions. We recently discovered that endothelial cells harbour a specific mechanism to limit the action of ZNF354C, whose function in endothelial cells is unknown. Given that ZNF354C has so far only been studied in bone and tumour, its function was determined in endothelial cells. ZNF354C is expressed in vascular cells and localises to the nucleus and cytoplasm. Overexpression of ZNF354C in human endothelial cells results in a marked inhibition of endothelial sprouting. RNA-sequencing of human microvascular endothelial cells with and without overexpression of ZNF354C revealed that the protein is a potent transcriptional repressor. ZNF354C contains an active KRAB domain which mediates this suppression as shown by mutagenesis analysis. ZNF354C interacts with dsDNA, TRIM28 and histones, as observed by proximity ligation and immunoprecipitation. Moreover, chromatin immunoprecipitation revealed that the ZNF binds to specific endothelial-relevant target-gene promoters. ZNF354C suppresses these genes as shown by CRISPR/Cas knockout and RNAi. Inhibition of endothelial sprouting by ZNF354C is dependent on the amino acids DV and MLE of the KRAB domain. These results demonstrate that ZNF354C is a repressive transcription factor which acts through a KRAB domain to inhibit endothelial angiogenic sprouting.
Author:James A. OoORCiDGND, Barnabas Irmer, Stefan GüntherORCiD, Timothy WarwickORCiDGND, Katalin Pálfi, Judit Izquierdo Ponce, Tom Teichmann, Beatrice Pflüger-MüllerORCiDGND, Ralf GilsbachORCiDGND, Ralf BrandesORCiDGND, Matthias LeisegangORCiDGND
Parent Title (English):Scientific reports
Publisher:Macmillan Publishers Limited, part of Springer Nature
Place of publication:[London]
Document Type:Article
Date of Publication (online):2020/11/05
Date of first Publication:2020/11/05
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/12/12
Tag:Angiogenesis; Gene regulation; Transcriptional regulatory elements
Issue:art. 19079
Article Number:19079
Page Number:14
First Page:1
Last Page:14
This work was supported by the Goethe University Frankfurt am Main, the German Centre for Cardiovascular Research (DZHK), the DFG excellence cluster Cardiopulmonary Institute (CPI) EXS2026, the DFG Transregio TRR267 (TPA04 & TPA06) and the SFB1039 (TP A01 to Ralf Brandes).
Open Access funding enabled and organized by Projekt DEAL.
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0