Institute of Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, 35043 Marburg, Germany.
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China.
Sci Adv. 2021 May 12;7(20). doi: 10.1126/sciadv.abf2229. Print 2021 May.
CpG islands (CGIs) are key regulatory DNA elements at most promoters, but how they influence the chromatin status and transcription remains elusive. Here, we identify and characterize SAMD1 (SAM domain-containing protein 1) as an unmethylated CGI-binding protein. SAMD1 has an atypical winged-helix domain that directly recognizes unmethylated CpG-containing DNA via simultaneous interactions with both the major and the minor groove. The SAM domain interacts with L3MBTL3, but it can also homopolymerize into a closed pentameric ring. At a genome-wide level, SAMD1 localizes to H3K4me3-decorated CGIs, where it acts as a repressor. SAMD1 tethers L3MBTL3 to chromatin and interacts with the KDM1A histone demethylase complex to modulate H3K4me2 and H3K4me3 levels at CGIs, thereby providing a mechanism for SAMD1-mediated transcriptional repression. The absence of SAMD1 impairs ES cell differentiation processes, leading to misregulation of key biological pathways. Together, our work establishes SAMD1 as a newly identified chromatin regulator acting at unmethylated CGIs.
CpG 岛（CGIs）是大多数启动子的关键调控 DNA 元件，但它们如何影响染色质状态和转录仍不清楚。在这里，我们鉴定并表征了 SAMD1（SAM 结构域蛋白 1）作为一种非甲基化 CGI 结合蛋白。SAMD1 具有一个非典型的翼状螺旋结构域，通过与主沟和小沟的同时相互作用，直接识别非甲基化的含 CpG 的 DNA。SAM 结构域与 L3MBTL3 相互作用，但它也可以自身聚合形成封闭的五聚体环。在全基因组水平上，SAMD1 定位于 H3K4me3 修饰的 CGI 上，作为一个抑制子发挥作用。SAMD1 将 L3MBTL3 固定在染色质上，并与 KDM1A 组蛋白去甲基化酶复合物相互作用，调节 CGIs 处的 H3K4me2 和 H3K4me3 水平，从而为 SAMD1 介导的转录抑制提供了一种机制。SAMD1 的缺失会损害 ES 细胞分化过程，导致关键生物途径的失调。总之，我们的工作确立了 SAMD1 作为一种新发现的在非甲基化 CGIs 上发挥作用的染色质调节剂。
