Center for Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
J Mol Biol. 2021 Jan 22;433(2):166722. doi: 10.1016/j.jmb.2020.11.021. Epub 2020 Nov 21.
The ZZ-type zinc finger and EF-hand domain protein 1 (ZZEF1) is a multidomain-containing protein. Mutations of ZZEF1 has been implicated in several kinds of human diseases such as diabetes and cancers. However, the function of the ZZEF protein remains largely unknown. Here we show that ZZEF1 functions as a histone H3 reader. The second ZZ domain of ZZEF1 (ZZEF1) binds to the N-terminus of histone H3 and is capable of accommodating common epigenetic marks on the H3 tail. The N-terminal amino acids, especially Ala1, of H3 and an acidic cavity of ZZEF1 are critical for the ZZ-H3 interaction. RNA-seq analysis in human lung cancer cell line H1299 reveals that downregulated genes upon ZZEF1 depletion are specifically enriched in genes regulated by Krüppel-like factors. Indeed, ZZEF1 physically interacts with KLF9 and KLF6, and regulates a common set of target genes of these transcription factors. Together, our findings suggest a model in which ZZEF1 binds to histone H3 tail and promotes KLF9/6-mediated gene regulation.
ZZ 型锌指和 EF 手域蛋白 1（ZZEF1）是一种具有多个结构域的蛋白。ZZEF1 的突变与多种人类疾病有关，如糖尿病和癌症。然而，ZZEF 蛋白的功能在很大程度上仍然未知。在这里，我们表明 ZZEF1 作为组蛋白 H3 的阅读器发挥作用。ZZEF1 的第二个 ZZ 结构域（ZZEF1）与组蛋白 H3 的 N 端结合，并能够容纳 H3 尾部上常见的表观遗传标记。H3 的 N 端氨基酸，特别是 Ala1，和 ZZEF1 的酸性腔对于 ZZ-H3 相互作用至关重要。人肺癌细胞系 H1299 的 RNA-seq 分析表明，ZZEF1 耗尽后下调的基因特别富集在受 Krüppel 样因子调控的基因中。事实上，ZZEF1 与 KLF9 和 KLF6 相互作用，并调节这些转录因子的一组共同的靶基因。总之，我们的研究结果表明，ZZEF1 结合组蛋白 H3 尾部并促进 KLF9/6 介导的基因调控。
