Tnrc18, or trinucleotide-repeat-containing 18, is a chromatin regulator with a poorly understood function. It plays a crucial role in recognizing H3K9me3, which is important for gene repression, heterochromatin formation, and silencing of endogenous retrotransposons, especially ERV class I elements such as LTR12. The carboxy-terminal bromo-adjacent homology (BAH) domain of TNRC18 acts as an H3K9me3-specific reader, and its amino-terminal segment recruits co-repressors like HDAC-Sin3-NCoR complexes to enforce optimal repression of ERVs [1].

In a mouse model, point mutagenesis disrupting the TNRC18(BAH)-mediated H3K9me3 engagement led to neonatal death. In multiple mammalian cell models, it caused derepressed expression of ERVs, which affected the cis-regulatory element landscape and gene-expression programs. These findings suggest that TNRC18 operates in an epigenetic pathway to silence evolutionarily young ERVs, influencing host genome integrity, transcriptomic regulation, immunity, and development [1].

In conclusion, TNRC18 is a key chromatin regulator involved in an important H3K9me3-sensing and regulatory pathway for silencing endogenous retrotransposons. The studies using mouse models have provided insights into its role in maintaining genome integrity, regulating gene expression, and its potential implications in immunity and development. Additionally, TNRC18 has been associated with diseases such as Fazio-Londe disease, acute promyelocytic leukemia, anterior uveitis, and potentially kidney function-related conditions, highlighting its significance in various disease areas [1,2,3,4,5,6].

References:

1. Zhao, Shuai, Lu, Jiuwei, Pan, Bo, Song, Jikui, Wang, Gang Greg. 2023. TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons. In Nature, 623, 633-642. doi:10.1038/s41586-023-06688-z. https://pubmed.ncbi.nlm.nih.gov/37938770/

2. Khani, Marzieh, Shamshiri, Hosein, Nafissi, Shahriar, Taheri, Hanieh, Elahi, Elahe. 2024. Identification of a mutation in TNRC18 in a patient with clinical features of Fazio-Londe disease. In Clinical case reports, 12, e8394. doi:10.1002/ccr3.8394. https://pubmed.ncbi.nlm.nih.gov/38188848/

3. Wang, Zheng, Wen, Lijun, Zhang, Ling, Jia, Zhilin, Chen, Suning. 2021. Identification of a novel TNRC18-RARA fusion in acute promyelocytic leukemia lacking t(15;17)(q24;q12)/PML-RARA. In Molecular carcinogenesis, 60, . doi:10.1002/mc.23276. https://pubmed.ncbi.nlm.nih.gov/33428799/

4. Xu, Jing, Li, He, Wang, Zhongwang, Liu, Yu, Niu, Ting. 2023. Venetoclax overcomes resistance to all-trans retinoic acid in a variant acute promyelocytic leukemia with TNRC18::RARA fusion. In Molecular carcinogenesis, 63, 553-557. doi:10.1002/mc.23671. https://pubmed.ncbi.nlm.nih.gov/38131515/

5. Koskimäki, Fredrika, Ahokas, Oona, Kajanne, Risto, Karjalainen, Minna K, Saarela, Ville. 2024. Genome-wide association study of anterior uveitis. In The British journal of ophthalmology, , . doi:10.1136/bjo-2024-326037. https://pubmed.ncbi.nlm.nih.gov/39732499/

6. Chu, Audrey Y, Tin, Adrienne, Schlosser, Pascal, Susztak, Katalin, Köttgen, Anna. 2017. Epigenome-wide association studies identify DNA methylation associated with kidney function. In Nature communications, 8, 1286. doi:10.1038/s41467-017-01297-7. https://pubmed.ncbi.nlm.nih.gov/29097680/