Mediator links epigenetic silencing of neuronal gene expression with x-linked mental retardation

被引:197
作者
Ding, Ning [1 ,2 ]
Zhou, Haiying [1 ,2 ]
Esteve, Pierre-Olivier [3 ]
Chin, Hang Gyeong [3 ]
Kim, Seokjoong [1 ,2 ]
Xu, Xuan [1 ,2 ]
Joseph, Sumy M. [4 ]
Friez, Michael J. [4 ]
Schwartz, Charles E. [4 ]
Pradhan, Sriharsa [3 ]
Boyer, Thomas G. [1 ,2 ]
机构
[1] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78245 USA
[2] Univ Texas Hlth Sci Ctr San Antonio, Inst Biotechnol, San Antonio, TX 78245 USA
[3] New England Biolabs Inc, Ipswich, MA 01938 USA
[4] Greenwood Genet Ctr, Greenwood, SC 29646 USA
关键词
D O I
10.1016/j.molcel.2008.05.023
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mediator occupies a central role in RNA polymerase 11 transcription as a sensor, integrator, and processor of regulatory signals that converge on protein-coding gene promoters. Compared to its role in gene activation, little is known regarding the molecular mechanisms and biological implications of Mediator as a transducer of repressive signals. Here we describe a protein interaction network required for extraneuronal gene silencing comprising Mediator, G9a histone methyltransferase, and the RE1 silencing transcription factor (REST; also known as neuron restrictive silencer factor, NRSF). We show that the MED12 interface in Mediator links REST with G9a-dependent histone H3K9 dimethylation to suppress neuronal genes in nonneuronal cells. Notably, missense mutations in MED12 causing the X-linked mental retardation (XLMR) disorders FG syndrome and Lujan syndrome disrupt its REST corepressor function. These findings implicate Mediator in epigenetic restriction of neuronal gene expression to the nervous system and suggest a pathologic basis for MED12-associated XLMR involving impaired REST-dependent neuronal gene regulation.
引用
收藏
页码:347 / 359
页数:13
相关论文
共 56 条
[1]   TFIIH is negatively regulated by cdk8-containing mediator complexes [J].
Akoulitchev, S ;
Chuikov, S ;
Reinberg, D .
NATURE, 2000, 407 (6800) :102-106
[2]   CoREST:: A functional corepressor required for regulation of neural-specific gene expression [J].
Andrés, ME ;
Burger, C ;
Peral-Rubio, MJ ;
Battaglioli, E ;
Anderson, ME ;
Grimes, J ;
Dallman, J ;
Ballas, N ;
Mandel, G .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (17) :9873-9878
[3]   REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis [J].
Ballas, N ;
Grunseich, C ;
Lu, DD ;
Speh, JC ;
Mandel, G .
CELL, 2005, 121 (04) :645-657
[4]   The yeast Mediator complex and its regulation [J].
Björklund, S ;
Gustafsson, CM .
TRENDS IN BIOCHEMICAL SCIENCES, 2005, 30 (05) :240-244
[5]   Mammalian Srb Mediator complex is targeted by adenovirus E1A protein [J].
Boyer, TG ;
Martin, MED ;
Lees, E ;
Ricciardi, RP ;
Berk, AJ .
NATURE, 1999, 399 (6733) :276-279
[6]   Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes [J].
Bruce, AW ;
Donaldson, IJ ;
Wood, IC ;
Yerbury, SA ;
Sadowski, MI ;
Chapman, M ;
Göttgens, B ;
Buckley, NJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (28) :10458-10463
[7]   REST - A MAMMALIAN SILENCER PROTEIN THAT RESTRICTS SODIUM-CHANNEL GENE-EXPRESSION TO NEURONS [J].
CHONG, JHA ;
TAPIARAMIREZ, J ;
KIM, S ;
TOLEDOARAL, JJ ;
ZHENG, YC ;
BOUTROS, MC ;
ALTSHULLER, YM ;
FROHMAN, MA ;
KRANER, SD ;
MANDEL, G .
CELL, 1995, 80 (06) :949-957
[8]   The mammalian Mediator complex and its role in transcriptional regulation [J].
Conaway, RC ;
Sato, S ;
Tomomori-Sato, C ;
Yao, TT ;
Conaway, JW .
TRENDS IN BIOCHEMICAL SCIENCES, 2005, 30 (05) :250-255
[9]   A genetic screen identifies novel polycomb group genes in Drosophila [J].
de Ayala Alonso, Andres Gaytan ;
Gutierrez, Luis ;
Fritsch, Cornelia ;
Papp, Bernadett ;
Beuchle, Dirk ;
Mueller, Juerg .
GENETICS, 2007, 176 (04) :2099-2108
[10]   The cyclin-dependent kinase 8 module sterically blocks Mediator interactions with RNA polymerase II [J].
Elmlund, Hans ;
Baraznenok, Vera ;
Lindahl, Martin ;
Samuelsen, Camilla O. ;
Koeck, Philip J. B. ;
Holmberg, Steen ;
Hebert, Hans ;
Gustafsson, Claes M. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (43) :15788-15793