朱恒《Cell》亮点文章 转录-蛋白组学取得重大突破（图）

　　

生物通报道，Johns Hopkins大学医学院药理与分子生物学系，眼科学系，神经科学系，高通量生物研究中心，细胞工程研究所等多处的科学家在蛋白-DNA相互作用的调控研究取得重大突破，相关成果文章Profiling the Human Protein-DNA Interactome Reveals ERK2 as a Transcriptional Repressor of Interferon Signaling发表在最新一期的Cell杂志上。

 

该文章发表后被本期的Cell列为亮点研究推荐，并邀请了德州大学西南医学中心的教授Melanie H. Cobb撰写评论文章，MAP-ping Unconventional Protein-DNA Interactions。

 

文章通讯作者是来自Johns Hopkins医学院的朱恒博士，Seth Blackshaw博士和 Jiang Qian博士，朱恒博士在药理与分子生物学系与生物高通量研究中心从事蛋白-DNA相互作用的研究，主要通过蛋白芯片等技术来研究蛋白对基因表达的调控作用。

 

随着基因组测序技术的发展，科学家们获得越来越多的基因组序列数据，大规模的基因组调控研究也随之进行，蛋白作为重要的调控因子越来越受到研究重视。

 

蛋白-DNA相互作用（Protein-DNA interactions，PDIs)是调控生命功能的重要机制，对细胞的分化发育、功能的维持以及细胞活性的维持都具有重大的意义。研究蛋白-DNA的相互作用是一个庞大的工程，研究课题包括，鉴定和绘制影响基因表达的蛋白图谱，尤其是对基因组有调控作用的蛋白的鉴定。

 

朱恒研究小组应用蛋白芯片，生物信息学等多种手段系统地分析了人类蛋白-DNA的作用图谱。他们在460个基因序列上发现了17718个蛋白-DNA作用现象，它们调控各种转录过程，这些蛋白可归类为4191种蛋白类别。

 

研究发现，很多PDIs都具有转录因子（Transcription factors，TFs）的功能，并且鉴定了大量先前没认识到的PDIs模式的转录因子。其中有300多种非传统的蛋白-DNA结合模式（unconventional DNA-binding proteins ，uDBPs)，包括 RNA-binding蛋白，线粒体蛋白，激酶蛋白。

 

其中一种独特的uDBPs是ERK2，它在干扰素γ诱导的基因表达中发挥转录抑制子的作用，这些数据表明，uDBPs在基因组的表达过程中具有重要的生物学意义。

 

ERK2

细胞外信号调节蛋白激酶(extracellular regulated protein, ERk)为MAPK家族重要成员,围绕肿瘤、血液等细胞领域的研究表明:ERK信号通路是多数生长因子、细胞因子调控细胞增殖的重要途径.进一步研究证实,ERK信号传导通路参与了细胞周期调控.

 

Erk2是可将胞外的生长和神经营养信号传到核内的蛋白激酶级连反应中的重要组分。

（生物通 小茜）

生物通推荐原文检索

Profiling the Human Protein-DNA Interactome Reveals ERK2 as a Transcriptional Repressor of Interferon Signaling

 

Shaohui Hu1, 4, 9, Zhi Xie2, 9, Akishi Onishi3, 4, 5, Xueping Yu2, Lizhi Jiang3, 4, 5, Jimmy Lin6, Hee-sool Rho1, 4, Crystal Woodard1, 4, Hong Wang3, 4, 5, Jun-Seop Jeong1, 4, Shunyou Long4, Xiaofei He1, 4, Herschel Wade7, Seth Blackshaw2, 3, 4, 5, ,  , Jiang Qian2, 8, ,   and Heng Zhu1, 4, 8, , 

 

1 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

2 Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

3 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

4 The Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

5 Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

6 Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

7 Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

8 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

9 These authors contributed equally to this work

【Summary】

Protein-DNA interactions (PDIs) mediate a broad range of functions essential for cellular differentiation, function, and survival. However, it is still a daunting task to comprehensively identify and profile sequence-specific PDIs in complex genomes. Here, we have used a combined bioinformatics and protein microarray-based strategy to systematically characterize the human protein-DNA interactome. We identified 17,718 PDIs between 460 DNA motifs predicted to regulate transcription and 4,191 human proteins of various functional classes. Among them, we recovered many known PDIs for transcription factors (TFs). We identified a large number of unanticipated PDIs for known TFs, as well as for previously uncharacterized TFs. We also found that over three hundred unconventional DNA-binding proteins (uDBPs)–which include RNA-binding proteins, mitochondrial proteins, and protein kinases–showed sequence-specific PDIs. One such uDBP, ERK2, acts as a transcriptional repressor for interferon gamma-induced genes, suggesting important biological roles for such proteins.