A Gro/TLE-NuRD corepressor complex facilitates Tbx20-dependent transcriptional repression.
A Gro/TLE-NuRD corepressor complex facilitates Tbx20-dependent transcriptional repression.
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DOI：
10.1021/pr400818c
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发表时间：
2013-12-06
影响因子：
4.4
通讯作者：
Conlon, Frank L.
中科院分区：
文献类型：
--
作者：
Kaltenbrun, Erin;Greco, Todd M.;Slagle, Christopher E.;Kennedy, Leslie M.;Li, Tuo;Cristea, Ileana M.;Conlon, Frank L.
心脏转录因子Tbx 20在脊椎动物心脏的正常形态发生发育中具有关键作用，其失调与人类先天性心脏病有关。虽然已经确定Tbx 20在胚胎心脏中通过不同基因程序的正向和负向调节发挥其功能，但还不清楚Tbx 20如何介导其靶基因的适当转录调节。在这里，使用组合蛋白质组学和生物信息学的方法，我们提出了第一个表征Tbx 20转录蛋白复合物。我们系统地研究了Tbx 20蛋白质-蛋白质相互作用的标记Tbx 20的免疫亲和纯化，然后使用GeLC-MS/MS，基因本体分类和功能网络分析的蛋白质组学分析。我们证明，Tbx 20与TLE/Groucho共阻遏物，核小体重塑和脱乙酰酶（NuRD）复合物的成员，染色质重塑ATP酶RUVBL 1/RUVBL 2，和T-box阻遏物Tbx 18组成的染色质重塑网络。我们确定，与TLE辅阻遏物的相互作用是通过Tbx 20中的eh 1结合基序介导的。此外，我们证明了该基序的消融导致未能正确组装阻遏网络并破坏Tbx 20在体内的功能。重要的是，我们验证了Tbx 20-TLE在小鼠胚胎心脏中的相互作用，并鉴定了由Tbx 20：TLE结合调节的发育基因，从而证实了Tbx 20-TLE阻遏物复合物在胚胎心脏发育中的主要作用。总之，这些研究提出了一种模型，其中Tbx 20与Gro/TLE-NuRD阻遏物复合物相关联，以防止形成心脏内的不适当基因激活。
The cardiac transcription factor Tbx20 has a critical role in the proper morphogenetic development of the vertebrate heart, and its misregulation has been implicated in human congenital heart disease. Although it is established that Tbx20 exerts its function in the embryonic heart through positive and negative regulation of distinct gene programs, it is unclear how Tbx20 mediates proper transcriptional regulation of its target genes. Here, using a combinatorial proteomic and bioinformatic approach, we present the first characterization of Tbx20 transcriptional protein complexes. We have systematically investigated Tbx20 protein-protein interactions by immunoaffinity purification of tagged Tbx20 followed by proteomic analysis using GeLC-MS/MS, gene ontology classification, and functional network analysis. We demonstrate that Tbx20 is associated with a chromatin remodeling network composed of TLE/Groucho co-repressors, members of the Nucleosome Remodeling and Deacetylase (NuRD) complex, the chromatin remodeling ATPases RUVBL1/RUVBL2, and the T-box repressor Tbx18. We determined that the interaction with TLE co-repressors is mediated via an eh1 binding motif in Tbx20. Moreover, we demonstrated that ablation of this motif results in a failure to properly assemble the repression network and disrupts Tbx20 function in vivo. Importantly, we validated Tbx20-TLE interactions in the mouse embryonic heart, and identified developmental genes regulated by Tbx20:TLE binding, thereby confirming a primary role for a Tbx20-TLE repressor complex in embryonic heart development. Together, these studies suggest a model in which Tbx20 associates with a Gro/TLE-NuRD repressor complex to prevent inappropriate gene activation within the forming heart.
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影响因子：
10.5
作者：
Chen, GQ;Fernandez, J;Courey, AJ
通讯作者：
Courey, AJ
DOI：
10.1016/j.bbrc.2007.07.109
发表时间：
2007-10-05
影响因子：
3.1
作者：
Ford, Jason;Odeyale, Oluwafemi;Shen, Chang-Hui
通讯作者：
Shen, Chang-Hui
影响因子：
2.7
作者：
Formaz-Preston, Ann;Ryu, Jae-Ryeon;Brook, William J.
通讯作者：
Brook, William J.
影响因子：
64.5
作者：
Fujita, N;Jaye, DL;Wade, PA
通讯作者：
Wade, PA
DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J