Corepressor for element-1-silencing transcription factor preferentially mediates gene networks underlying neural stem cell fate decisions.
The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) silences neuronal genes in neural stem cells (NSCs) and nonneuronal cells through its role as a dynamic modular platform for recruitment of transcriptional and epigenetic regulatory cofactors to RE1-containing promoters. In embryonic stem cells, the REST regulatory network is highly integrated with the transcriptional circuitry governing self-renewal and pluripotency, although its exact functional role is unclear. The C-terminal cofactor for REST, CoREST, also acts as a modular scaffold, but its cell type-specific roles have not been elucidated. We used chromatin immunoprecipitation-on-chip to examine CoREST and REST binding sites in NSCs and their proximate progenitor species. In NSCs, we identified a larger number of CoREST (1,820) compared with REST (322) target genes. The majority of these CoREST targets do not contain known RE1 motifs. Notably, these CoREST target genes do play important roles in pluripotency networks, in modulating NSC identity and fate decisions and in epigenetic processes previously associated with both REST and CoREST. Moreover, we found that NSC-mediated developmental transitions were associated primarily with liberation of CoREST from promoters with transcriptional repression favored in less lineage-restricted radial glia and transcriptional activation favored in more lineage-restricted neuronal-oligodendrocyte precursors. Clonal NSC REST and CoREST gene manipulation paradigms further revealed that CoREST has largely independent and previously uncharacterized roles in promoting NSC multilineage potential and modulating early neural fate decisions.
Abrajano
Joseph J
JJ
Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Qureshi
Irfan A
IA
Gokhan
Solen
S
Molero
Aldrin E
AE
Zheng
Deyou
D
Bergman
Aviv
A
Mehler
Mark F
MF
D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000099229:RE1-Silencing Transcription Factor
D056970:Co-Repressor Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C485650:Rcor2 protein, mouse
Neurosci Lett. 2009 Dec 4;466(2):73-80
19679163
J Biol Chem. 2000 Mar 31;275(13):9461-7
10734093
Biochem J. 2008 Sep 15;414(3):327-41
18717648
Science. 1995 Mar 3;267(5202):1360-3
7871435
Stem Cells. 2008 Aug;26(8):1951-60
18483421
Cell. 2005 May 20;121(4):645-657
15907476
Genes Dev. 2007 Oct 15;21(20):2545-57
17938240
J Mol Neurosci. 2006;29(3):227-39
17085781
Mol Cell Biol. 2006 Mar;26(5):1666-78
16478988
Cell. 1995 Mar 24;80(6):949-57
7697725
Dev Growth Differ. 2008 Jun;50 Suppl 1:S97-103
18430159
Nucleic Acids Res. 2004 Jun 24;32(11):e88
15247321
PLoS One. 2009 Dec 07;4(12):e7936
19997604
Curr Opin Neurobiol. 2005 Oct;15(5):500-6
16150588
Nature. 2008 May 8;453(7192):223-7
18362916
Cell. 2005 Sep 23;122(6):947-56
16153702
Biochem Biophys Res Commun. 2008 Dec 26;377(4):1031-5
18854179
Dev Biol. 2004 May 15;269(2):580-94
15110721
EMBO J. 1994 Apr 15;13(8):1799-805
7909512
Curr Opin Neurobiol. 2010 Feb;20(1):29-36
20137907
Stem Cells Dev. 2009 Jun;18(5):707-16
18724799
Dev Cell. 2007 Aug;13(2):283-97
17681138
Development. 2003 Jun;130(11):2505-12
12702663
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9873-8
10449787
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2422-7
16461918
Stem Cells. 2008 Oct;26(10):2467-74
18635867
Crit Rev Oncol Hematol. 2008 Jan;65(1):43-53
17644000
Stem Cells. 2007 Feb;25(2):354-63
17082226
Nat Genet. 1998 Oct;20(2):136-42
9771705
Genome Res. 2006 Oct;16(10):1208-21
16963704
Cell Stem Cell. 2007 Nov;1(5):515-28
18371391
Oncogene. 2004 Dec 16;23(58):9392-400
15558011
Dev Cell. 2007 Jun;12(6):843-4
17543855
J Neurosci. 2007 May 16;27(20):5461-73
17507568
Methods Enzymol. 2004;376:315-34
14975315
Dev Neurosci. 2004 Mar-Aug;26(2-4):181-96
15711059
Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21900-5
19955426
Dev Biol. 1998 Dec 15;204(2):577-91
9882491
PLoS One. 2009 Nov 03;4(11):e7665
19888342
Nat Genet. 2006 Apr;38(4):431-40
16518401
Nat Rev Genet. 2007 Jan;8(1):35-46
17173056
J Biol Chem. 2003 Nov 7;278(45):44808-15
12947105
Exp Cell Res. 2005 Jun 10;306(2):343-8
15925590
Genes Dev. 2007 May 15;21(10):1141-4
17504932
Genome Res. 2009 Jun;19(6):994-1005
19401398
Nature. 2010 Jan 28;463(7280):474-84
20110991
J Neurosci. 2008 Oct 15;28(42):10674-86
18923043
Genome Biol. 2006;7(9):R85
17002790
J Neurosci. 2005 Sep 7;25(36):8311-21
16148239
Nature. 2008 Oct 23;455(7216):1061-8
18772890
Hum Mol Genet. 2008 Apr 15;17(R1):R23-7
18632692
J Neurosci. 2007 Jun 20;27(25):6729-39
17581960
Nature. 2009 Feb 26;457(7233):E5-6; discussion E7
19242418
Nat Genet. 2003 Sep;35(1):76-83
12881722
Science. 2007 Jun 8;316(5830):1497-502
17540862
Nature. 1999 Oct 14;401(6754):670-7
10537105
J Neurosci Res. 2000 Feb 1;59(3):312-20
10679766
Methods. 2002 Jan;26(1):37-47
12054903
Nature. 2008 Sep 18;455(7211):401-5
18724358
Science. 2005 Jan 28;307(5709):596-600
15681389
PLoS Biol. 2008 Oct 28;6(10):e256
18959480
Mol Cell Biol. 2008 Jun;28(12):3995-4003
18391013
J Neurosci. 2006 Oct 25;26(43):10967-83
17065439
J Neurosci. 1998 Dec 1;18(23):9800-11
9822739
Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10458-63
15240883
J Cell Sci. 2008 Aug 15;121(Pt 16):2629-34
18653541
Genes Dev. 2007 Apr 1;21(7):744-9
17403776
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16273-8
12461181
Science. 2007 Dec 21;318(5858):1917-20
18029452
Development. 2009 May;136(9):1443-52
19363151
J Neurosci Res. 1999 Apr 15;56(2):131-45
10494102