a member of the bHLH (basic helix-loop-helix) family of transcription factors. This protein is predicted to span 179 amino acid residues and contains a bHLH domain and an arginine-rich sequence that may facilitate DNA binding. Function TCF21 encodes a transcription factor of the basic helix-loop-helix (bHLH) family, which manages cell-fate specification, commitment and differentiation in various cell lineages during development. The TCF21 product is mesoderm-specific and expressed in embryonic epicardium, mesenchyme-derived tissues of lung, gut, gonad, and both mesenchymal and glomerular epithelial cells in the kidney. TCF21 is essential for regulating properties of the mesenchyme that are critically important for several aspects of lung and kidney morphogenesis. TCF21 is also essential for cardiac fibroblast cell fate, as demonstrated by the failed development of cardiac fibroblasts in mice lacking TCF21. In the absence of TCF21, these fibroblast progenitor cells do not undergo epithelial-to-mesenchymal transition (EMT). While TCF21-expressing epicardial cells are initially multipotent, they become committed to the fibroblast lineage over time. Those TCF21-expressing cells that do not commit to the fibroblast lineage lose this expression and remain undifferentiated epicardial cells or coronary vascular smooth muscle cells. TCF21 is expressed in mesodermal cells in the proepicardial organ that give rise to coronary artery smooth muscle cells (SMC) and loss of TCF21 results in increased expression of smooth muscle markers by cells on the heart surface consistent with premature SMC differentiation. This suggests that early expression of TCF21 is important for expansion of the SMC compartment of the coronary circulation, with persistent TCF21 expression being required for cardiac fibroblast development. TCF21 activation is directed by an antisense long non-coding RNA, TARID (TCF21 antisense RNA inducing demethylation). TARID activates TCF21 expression by inducing promoter demethylation and affects expression levels of target genes by functioning as epigenetic regulators of chromatin structure through interactions with histone modifiers, chromatin remodeling complexes, transcriptional regulators, and/or DNA methylation machinery. Role in development Since the identification of Tcf21 significance in various cell lineages, further research has expanded understanding of the essential roles of this gene. TCF21 is essential for regulating properties of the mesenchyme that are critically important for several aspects of lung and kidney morphogenesis. Null TCF21 mutant mice are born but die shortly after due to severely hypoplastic lungs and kidneys that lack alveoli and mature glomeruli. While TCF21 is exclusively expressed in the mesenchyme and podocytes, major defects are observed in adjacent epithelia of TCF21 mutant mice.