奥地利科学院分子医学CeMM研究中心Stefan Kubicek团队近日取得一项新成果。他们发现了MTHFD1与BRD4的相互作用与叶酸代谢与转录调控之间的联系。这一成果发表在2019年出版的国际学术期刊《Nature Genetics》上。

研究小组描述了两个互补的基于BRD4基因组和物理相互作用的筛选,结果瞄向了叶酸代谢通路酶MTHFD1 (methylenetetrahydrofolate脱氢酶,cyclohydrolase formyltetrahydrofolate合成酶1)。显示MTHFD1的一小部分存在于核中，通过与BRD4的直接相互作用将其募集到不同的基因组位点。抑制BRD4或MTHFD1导致相似的核代谢物合成和基因表达的变化;药理抑制剂的两个途径加强影响体外和体内癌细胞生存能力。他们发现MTHFD1和其他代谢相关的酶是染色质相关联的，表明了核代谢在控制基因表达中的直接作用。

研究人员表示，组蛋白乙酰读取器含溴结构域蛋白4（BRD4）是染色质结构和转录的重要调节因子，但调节其活性的因子尚不清楚。

附：英文原文

Title: MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation

Author: Sara Sdelci, Andr F. Rendeiro, Philipp Rathert, Wanhui You, Jung-Ming G. Lin, Anna Ringler, Gerald Hofsttter, Herwig P. Moll, Bettina Grtl, Matthias Farlik, Sandra Schick, Freya Klepsch, Matthew Oldach, Pisanu Buphamalai, Fiorella Schischlik, Peter Mjek, Katja Parapatics, Christian Schmidl, Michael Schuster, Thomas Penz, Dennis L. Buckley, Otto Hudecz, Richard Imre, Shuang-Yan Wang, Hans Michael Maric, Robert Kralovics, Keiryn L. Bennett, Andre C. Mller, Karl Mechtler, Jrg Menche, James E. Bradner, Georg E. Winter, Kristaps Klavins, Emilio Casanova, Christoph Bock, Johannes Zuber, Stefan Kubicek

Issue&Volume: Volume 51 Issue 6, June 2019

Abstract: The histone acetyl reader bromodomain-containing protein 4 (BRD4) is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1 (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1). We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression; pharmacological inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin associated suggests a direct role for nuclear metabolism in the control of gene expression.

DOI: 10.1038/s41588-019-0413-z

Source:https://www.nature.com/articles/s41588-019-0413-z