Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, and.
J Biol Chem. 2012 Mar 23;287(13):10089-10098. doi: 10.1074/jbc.M111.313965. Epub 2012 Jan 30.
Histone methylation on lysine residues is believed to function primarily as docking sites to recruit specific proteins termed as histone code "readers" or "effectors." Each lysine residue can be mono-, di, and tri-methylated and different methylation states can have different effect on chromatin function. While an increasing number of proteins have been identified and characterized as specific effectors for methylated histones, very few of the proteins are known to recognize a particular state of methylation. In this study, we identified nardilysin (NRDc), a member of M16 family metalloendopeptidases, as a novel dimethyl-H3K4 (H3K4me2)-binding protein. Among three methylated states, NRDc binds preferentially H3K4me2 both in vitro and in vivo. Biochemical purification demonstrated that NRDc interacts with the NCoR/SMRT corepressor complex. We identified target genes repressed by NRDc through microarray. We showed that NRDc is physically associated with and recruits the NCoR complex to some of the repressed genes and this association correlates with binding of H3K4me2. Thus, our study has identified a novel H3K4me2-binding protein and revealed a role of NRDc in transcriptional regulation.
赖氨酸残基上的组蛋白甲基化被认为主要作为结合位点，募集特定的蛋白质，这些蛋白质被称为组蛋白密码的“读取器”或“效应器”。每个赖氨酸残基可以单甲基化、二甲基化和三甲基化，不同的甲基化状态对染色质功能有不同的影响。虽然已经鉴定和表征了越来越多的蛋白质作为甲基化组蛋白的特异性效应物，但很少有蛋白质被认为能识别特定的甲基化状态。在这项研究中，我们鉴定了 NARDILYSIN（NRDc），一种 M16 家族金属内肽酶，为一种新型二甲基-H3K4（H3K4me2）结合蛋白。在三种甲基化状态中，NRDc 在体外和体内都优先结合 H3K4me2。生化纯化表明，NRDc 与 NCoR/SMRT 核心抑制复合物相互作用。我们通过微阵列鉴定了被 NRDc 抑制的靶基因。我们表明，NRDc 与一些被抑制的基因相关，并招募 NCoR 复合物，这种关联与 H3K4me2 的结合有关。因此，我们的研究鉴定了一种新型的 H3K4me2 结合蛋白，并揭示了 NRDc 在转录调控中的作用。
