ZNF354C is a transcriptional repressor that inhibits endothelial angiogenic sprouting

Abstract

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.

ZNF354C Mediated by DNMT1 Ameliorates Lung Ischemia-Reperfusion Oxidative Stress Injury by Reducing TFPI Promoter Methylation to Upregulate TFPI

“…A previous study reported that ZNF354C is a key transcriptional factor in carcinogenesis and the development of esophageal squamous cell carcinoma (ESCC) by regulating targets genes [ 67 ]. Recently, a study revealed that ZNF354C is expressed in vascular cells, while ZNF354C overexpression inhibits the endothelial sprouting by binding to specific endothelial relevant target gene promoter [ 18 ]. In our study, we also proved that ZNF354C, as a transcriptional factor, could directly bind the promoter of TFPI.…”

“…Zinc finger proteins (ZNF) are a class of transcription factors with multiple functions [ 16 ]. Specifically, ZNF354C has been found to have a critical role in bone and tumors [ 17 , 18 ]. To further investigate the possible mechanisms of TFPI in LIRI, we applied bioinformatic analysis to predict the potential proteins that can bind to the TFPI promoter and concluded that ZNF354C may have a direct targeting regulatory role with the TFPI promoter.…”

Distinct Differences in Gene Expression Profiles in Early and Late Stage Rhodesiense HAT Individuals in Malawi

“…Among the 632 CDS, ZNF354C was upregulated (log2FC 1.9) in stage 1 only, whereas TCN1 (log2FC 2.0) and MAGI3 (log2FC 1.4) were upregulated in stage 2 blood only (Fig 4B) . Overexpression of ZNF354C has a crucial role in inhibition of endothelial cell sprouting (31). TCN1 expression in blood is negatively associated with poor verbal memory performance (32).…”

“…in stage 2 blood only (Fig 4B). Overexpression of ZNF354C has a crucial role in inhibition of endothelial cell sprouting(31). TCN1 expression in blood is negatively associated with poor verbal memory performance(32).…”

Functional Analysis of Haplotypes and Promoter Activity at the 5’ Region of the ADH7 Gene

“…ZNF354C acts as an inhibitory transcription factor in its KRAB domain dependent on speci c amino acids. Overexpression of ZNF354C leads to transcriptional inhibition of many genes (Oo et al 2020). The expression among the three cell lines was not the same in the regions of-310 ~ 560bp, -1203~-1369bp, and-1369~-1626bp.…”