The Role of Transcription Factor 21 in Epicardial Cell Differentiation and the Development of Coronary Heart Disease

Abstract

Transcription factor 21 (TCF21) is specific for mesoderm and is expressed in the embryos' mesenchymal derived tissues, such as the epicardium. It plays a vital role in regulating cell differentiation and cell fate specificity through epithelial-mesenchymal transformation during cardiac development. For instance, TCF21 could promote cardiac fibroblast development and inhibit vascular smooth muscle cells (VSMCs) differentiation of epicardial cells. Recent large-scale genome-wide association studies have identified a mass of loci associated with coronary heart disease (CHD). There is mounting evidence that TCF21 polymorphism might confer genetic susceptibility to CHD. However, the molecular mechanisms of TCF21 in heart development and CHD remain fundamentally problematic. In this review, we are committed to providing a detailed introduction of the biological roles of TCF21 in epicardial fate determination and the development of CHD.

Identification of enhancer regulatory elements that direct epicardial gene expression during zebrafish heart regeneration

“…However, AP-1 motifs are common within regulatory sequences (Umer et al, 2019), and thus a requirement for these motifs might not reflect specificity for regeneration-related gene expression. Other enriched motifs highlight pathways and TFs known to regulate epicardium development and/or regeneration: Tcf21 (Hu et al, 2020), Hippo/Yap pathway (TEA domain family members, TEADs) (Xiao et al, 2018), C/EBPb (CCAAT/enhancer-binding protein b)(Huang et al, 2012), Tgfβ pathway (Smad2/3/4) (Chablais and Jazwinska, 2012), Hedgehog pathway (GLI family zinc finger 2, Gli2) (Choi et al, 2013; Sugimoto et al, 2017; Wang et al, 2015). Additional implicated TFs that have not been connected to epicardial functions include NFATC1 (Nuclear Factor of Activated T Cells 1), Nrf2 (Nuclear factor-E2-related factor 2), Stat3, FoxO1 (Forkhead box O1), FoxO3, FoxO6, and ZBTB7A (Zinc Finger and BTB Domain Containing 7A) (Figure 2D).…”

Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of Fragile X Syndrome

“…To further explore how these gene expression changes might have happened, we next performed transcription factor (TF) target enrichment analysis to identify potential upstream TFs responsible for observed changes in gene expression of Nutlin-3-treated Fmr1 KO mice. Our analysis showed that the top TFs are mainly involved in stem cell fate specification (such as MEOX1, MEOX2, PRRX1, BNC2, SOX18 and TWIST1) [47–51] and/or extra cellular matrix organization (such as HEYL, TBX18, PRRX1, PRRX2 and TCF21)[52–54] ( Fig. 6a;; Additional file 3: Fig.…”

Post-Transcriptional Regulation of Molecular Determinants during Cardiogenesis

“…At transcriptional level, three distinct transcription factors have been reported to play essential roles in proepicardium and epicardium development, namely, Tcf21, Tbx18 and Wt1. Tcf21 is a transcription factor of the “helix-loop-helix” (HLH) family that is expressed in different tissues derived from the mesoderm, including therein the epicardium [ 213 , 214 ]. In the epicardium, one of the main functions of Tcf1 is to regulate the EMT and the subsequent differentiation and specification of cells derived from the epicardium (EPDC) towards different cell types [ 214 ].…”