Ctcfl, also known as BORIS (Brother of Regulator of Imprinted Sites), is a paralog of CTCF. It is normally transiently expressed in pre-meiotic male germ cells and plays a unique role in spermatogenesis by regulating the expression of testis-specific genes. It can act as a transcription factor and is involved in epigenetic reprogramming of chromatin [1,3,4].

In mouse models, inappropriate expression of Ctcfl using a tetracycline-inducible transgene negatively impacts fetal development, causing early postnatal lethality. The affected pups show severe vascular abnormalities and localized hemorrhages in the brain similar to human cerebral cavernous malformations (CCM) and arteriovenous malformations (AVM). Ctcfl transgenic animals also exhibit abnormal expression of CCM-related proteins [2]. In melanoma cells, ectopic expression of BORIS/CTCFL leads to chromatin accessibility alterations, promoting a pro-invasive transcriptional signature. In gastric cancer, CTCFL promotes cell proliferation, migration, and invasion via activating DPPA2. In neuroblastoma, BORIS/CTCFL expression activates the TGFβ signaling cascade and induces Drp1-mediated mitochondrial fission [5,6,7].

In conclusion, Ctcfl is crucial for spermatogenesis and its abnormal expression is associated with various diseases including vascular malformations, melanoma, gastric cancer, and neuroblastoma. Mouse models, especially those with inducible expression of Ctcfl, have been valuable in revealing its role in fetal development and disease-related biological processes, providing insights into potential therapeutic targets for these diseases.

References:

1. Debaugny, Roxanne E, Skok, Jane A. 2020. CTCF and CTCFL in cancer. In Current opinion in genetics & development, 61, 44-52. doi:10.1016/j.gde.2020.02.021. https://pubmed.ncbi.nlm.nih.gov/32334335/

2. Sati, Leyla, Soygur, Bikem, Goksu, Ethem, Bassorgun, Cumhur Ibrahim, McGrath, James. 2021. CTCFL expression is associated with cerebral vascular abnormalities. In Tissue & cell, 72, 101528. doi:10.1016/j.tice.2021.101528. https://pubmed.ncbi.nlm.nih.gov/33756271/

3. Tong, Xin, Gao, Yang, Su, Zhongjing. 2024. Interaction of CTCF and CTCFL in genome regulation through chromatin architecture during the spermatogenesis and carcinogenesis. In PeerJ, 12, e18240. doi:10.7717/peerj.18240. https://pubmed.ncbi.nlm.nih.gov/39430552/

4. Pugacheva, Elena M, Bhatt, Dharmendra Nath, Rivero-Hinojosa, Samuel, Ren, Bing, Lobanenkov, Victor V. 2024. BORIS/CTCFL epigenetically reprograms clustered CTCF binding sites into alternative transcriptional start sites. In Genome biology, 25, 40. doi:10.1186/s13059-024-03175-0. https://pubmed.ncbi.nlm.nih.gov/38297316/

5. Moscona, Roy, Janssen, Sanne Marlijn, Elchebly, Mounib, Rubin, Eitan, Spatz, Alan. 2023. BORIS/CTCFL-mediated chromatin accessibility alterations promote a pro-invasive transcriptional signature in melanoma cells. In Pigment cell & melanoma research, 36, 299-313. doi:10.1111/pcmr.13089. https://pubmed.ncbi.nlm.nih.gov/37082838/

6. Yao, Haibo, Shao, Qinshu, Shao, Yanfei. 2021. Transcription Factor CTCFL Promotes Cell Proliferation, Migration, and Invasion in Gastric Cancer via Activating DPPA2. In Computational and mathematical methods in medicine, 2021, 9097931. doi:10.1155/2021/9097931. https://pubmed.ncbi.nlm.nih.gov/34721660/

7. Makani, Venkata Krishna Kanth, Mendonza, Jolly Janette, Edathara, Prajitha Mohandas, Yerramsetty, Suresh, Pal Bhadra, Manika. 2021. BORIS/CTCFL expression activates the TGFβ signaling cascade and induces Drp1 mediated mitochondrial fission in neuroblastoma. In Free radical biology & medicine, 176, 62-72. doi:10.1016/j.freeradbiomed.2021.09.010. https://pubmed.ncbi.nlm.nih.gov/34534628/