Ahctf1-KO Mouse

Ahctf1, also known as ELYS, encodes a large multifunctional nucleoporin protein. It is essential for nuclear pore assembly, mitosis, and is involved in pathways like WNT signaling [2,3,4]. Its functions are crucial for normal embryonic development and cell cycle regulation, making genetic models valuable for studying its role.

In zebrafish models, deficiency or dysfunction of Ahctf1 impairs nuclear pore complex (NPC) assembly, maternal transcription factors' nuclear transport, and the onset of zygotic genome activation (ZGA) during early embryogenesis [1]. In a zebrafish hepatocellular carcinoma (HCC) model, reducing ahctf1 gene dosage by 50% decreases liver volume in cancer-related hyperplasia, as it impairs nuclear pore formation, mitotic spindle assembly, and chromosome segregation, leading to DNA damage and activation of a Tp53-dependent transcriptional programme [2]. In colon cancer cells, AHCTF1 regulates the oncogenic super-enhancer-mediated gating of MYC to nuclear pores, increasing MYC transcript export rates [3]. A WNT/β-catenin-AHCTF1-CTCF-eRNA circuit in HCT-116 cells enables the oncogenic super-enhancer to promote pathological cell growth by trafficking the active MYC gene [4].

In conclusion, Ahctf1 plays vital roles in NPC assembly, mitosis, and gene expression regulation, especially in processes like ZGA during embryogenesis and in cancer-related cell growth. Studies using zebrafish and cell-based models have provided insights into its functions in these biological processes and disease conditions, highlighting its potential as a therapeutic target, particularly in cancer [1,2,3,4].

References:

1. Shen, Weimin, Gong, Bo, Xing, Cencan, Wu, Xiaotong, Meng, Anming. 2022. Comprehensive maturity of nuclear pore complexes regulates zygotic genome activation. In Cell, 185, 4954-4970.e20. doi:10.1016/j.cell.2022.11.011. https://pubmed.ncbi.nlm.nih.gov/36493774/

2. Morgan, Kimberly J, Doggett, Karen, Geng, Fansuo, Gong, Zhiyuan, Heath, Joan K. 2023. ahctf1 and kras mutations combine to amplify oncogenic stress and restrict liver overgrowth in a zebrafish model of hepatocellular carcinoma. In eLife, 12, . doi:10.7554/eLife.73407. https://pubmed.ncbi.nlm.nih.gov/36648336/

3. Scholz, Barbara A, Sumida, Noriyuki, de Lima, Carolina Diettrich Mallet, Göndör, Anita, Ohlsson, Rolf. 2019. WNT signaling and AHCTF1 promote oncogenic MYC expression through super-enhancer-mediated gene gating. In Nature genetics, 51, 1723-1731. doi:10.1038/s41588-019-0535-3. https://pubmed.ncbi.nlm.nih.gov/31784729/

4. Chachoua, Ilyas, Tzelepis, Ilias, Dai, Hao, Mehmood, Rashid, Göndör, Anita. 2022. Canonical WNT signaling-dependent gating of MYC requires a noncanonical CTCF function at a distal binding site. In Nature communications, 13, 204. doi:10.1038/s41467-021-27868-3. https://pubmed.ncbi.nlm.nih.gov/35017527/