Tcf20, encoding a transcriptional co-regulator, is a nuclear chromatin-binding protein involved in the regulation of gene expression. Structurally related to RAI1, it is part of the TCF20/PHF14 chromatin complex, which plays a vital role in epigenetic and transcriptional regulation [1,4].

In Tcf20 knockout (Tcf20-/-) mice, impaired neural development and post-birth death were observed. Heterozygous mice showed higher CCl4-induced liver fibrosis, differential expression of extracellular matrix-related genes, and abnormal behavioral patterns similar to autism-like phenotypes. Tcf20-/-embryonic livers and mouse embryonic fibroblast cells had differential expression of mitochondrial oxidative phosphorylation chain proteins, increased mitochondrial metabolic activity, and altered citric acid cycle metabolites. These findings parallel those in humans with TCF20 pathogenic variants, indicating a role in fibrogenesis and mitochondrial metabolism [2]. In addition, TCF20 deletion in mice significantly reduced the number of neurons, leading to abnormal brain functions. Transcriptome analysis showed that the DNA demethylation factor TDG is a downstream target gene of TCF20, and TDG and TCF-4 can rescue the deficient neurogenesis of TCF20 knockdown brains, suggesting TCF20 is essential for neurogenesis and its loss may be associated with autism-spectrum disorder (ASD) [3].

In conclusion, Tcf20 is crucial for neural development, liver fibrogenesis, and mitochondrial metabolism. Mouse models, especially Tcf20 knockout models, have been instrumental in revealing its role in neurodevelopmental disorders like ASD, as well as in liver-related fibrogenic and metabolic processes. These findings provide important insights into the underlying mechanisms of these diseases and potential therapeutic targets.

References:

1. Vetrini, Francesco, McKee, Shane, Rosenfeld, Jill A, Lupski, James R, Liu, Pengfei. 2019. De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome. In Genome medicine, 11, 12. doi:10.1186/s13073-019-0623-0. https://pubmed.ncbi.nlm.nih.gov/30819258/

2. Córdoba-Jover, Bernat, Ribera, Jordi, Portolés, Irene, Jiménez, Wladimiro, Morales-Ruiz, Manuel. 2023. Tcf20 deficiency is associated with increased liver fibrogenesis and alterations in mitochondrial metabolism in mice and humans. In Liver international : official journal of the International Association for the Study of the Liver, 43, 1822-1836. doi:10.1111/liv.15640. https://pubmed.ncbi.nlm.nih.gov/37312667/

3. Feng, Chao, Zhao, Jinyue, Ji, Fen, Chen, Yihui, Jiao, Jianwei. 2020. TCF20 dysfunction leads to cortical neurogenesis defects and autistic-like behaviors in mice. In EMBO reports, 21, e49239. doi:10.15252/embr.201949239. https://pubmed.ncbi.nlm.nih.gov/32510763/

4. Dominguez, Gaea, Wu, Yongji, Zhou, Jian. 2024. Epigenetic Regulation and Neurodevelopmental Disorders: From MeCP2 to the TCF20/PHF14 Complex. In Genes, 15, . doi:10.3390/genes15121653. https://pubmed.ncbi.nlm.nih.gov/39766920/