Zzef1, the ZZ-type zinc finger and EF-hand domain protein 1, is a multidomain-containing protein. Mutations in ZZEF1 have been associated with diseases like diabetes and cancers [1]. It functions as a histone H3 reader, with its second ZZ domain (ZZEF1ZZ2) binding to the N-terminus of histone H3, enabling it to accommodate common epigenetic marks on the H3 tail. RNA-seq analysis in human lung cancer cell line H1299 shows that ZZEF1 depletion leads to downregulation of genes enriched in those regulated by Krüppel-like factors. ZZEF1 physically interacts with KLF9 and KLF6, regulating their common target genes, suggesting it promotes KLF9/6-mediated gene regulation [1].

In an autosomal-dominant macular dystrophy study, a 560 kb tandem duplication on chromosome 17 led to the formation of a novel ZZEF1-ALOX15 fusion gene. Functional studies in mouse retina showed that this fusion gene, driven by the ZZEF1 promoter, caused retinal disorganization, photoreceptor, and RPE damage due to mislocalization and overexpression of ALOX15 [2].

In conclusion, ZZEF1 plays crucial roles in histone-mediated gene regulation and, through the formation of fusion genes, can be involved in the development of macular dystrophy. Its function as a histone reader and its interaction with transcription factors highlight its significance in normal biological processes and disease-associated gene regulation.

References:

1. Yu, Yucong, Tencer, Adam, Xuan, Hongwen, Kutateladze, Tatiana G, Shi, Xiaobing. 2020. ZZEF1 is a Histone Reader and Transcriptional Coregulator of Krüppel-Like Factors. In Journal of molecular biology, 433, 166722. doi:10.1016/j.jmb.2020.11.021. https://pubmed.ncbi.nlm.nih.gov/33227311/

2. Adele, Rabiat, Hussein, Rowaida, Tavares, Erika, Héon, Elise, Vincent, Ajoy. 2024. Autosomal-dominant macular dystrophy linked to a chromosome 17 tandem duplication. In JCI insight, 9, . doi:10.1172/jci.insight.178768. https://pubmed.ncbi.nlm.nih.gov/39436697/