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_ZZ2) 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_ZZ2 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 手结构域蛋白 1 (ZZEF1) 是一种含有多结构域的蛋白质。ZZEF1 的突变与糖尿病和癌症等多种人类疾病有关。然而，ZZEF 蛋白的功能仍然很大程度上未知。在这里，我们展示了 ZZEF1 作为组蛋白 H3 阅读器的功能。ZZEF1 的第二个 ZZ 结构域 (ZZEF1 _ZZ2 ) 与组蛋白 H3 的 N 端结合，能够容纳 H3 尾部的常见表观遗传标记。H3 的 N 端氨基酸，尤其是 Ala1 和 ZZEF1 _{ZZ2的酸性腔}对 ZZ-H3 相互作用至关重要。人肺癌细胞系 H1299 中的 RNA-seq 分析表明，ZZEF1 缺失后下调的基因特别富含受 Krüppel 样因子调节的基因。事实上，ZZEF1 与 KLF9 和 KLF6 发生物理相互作用，并调节这些转录因子的一组常见靶基因。总之，我们的研究结果表明 ZZEF1 与组蛋白 H3 尾部结合并促进 KLF9/6 介导的基因调控的模型。