Role of the transcriptional corepressor Bcor in embryonic stem cell differentiation and early embryonic development.
Bcor (BCL6 corepressor) is a widely expressed gene that is mutated in patients with X-linked Oculofaciocardiodental (OFCD) syndrome. BCOR regulates gene expression in association with a complex of proteins capable of epigenetic modification of chromatin. These include Polycomb group (PcG) proteins, Skp-Cullin-F-box (SCF) ubiquitin ligase components and a Jumonji C (Jmjc) domain containing histone demethylase. To model OFCD in mice and dissect the role of Bcor in development we have characterized two loss of function Bcor alleles. We find that Bcor loss of function results in a strong parent-of-origin effect, most likely indicating a requirement for Bcor in extraembryonic development. Using Bcor loss of function embryonic stem (ES) cells and in vitro differentiation assays, we demonstrate that Bcor plays a role in the regulation of gene expression very early in the differentiation of ES cells into ectoderm, mesoderm and downstream hematopoietic lineages. Normal expression of affected genes (Oct3/4, Nanog, Fgf5, Bmp4, Brachyury and Flk1) is restored upon re-expression of Bcor. Consistent with these ES cell results, chimeric animals generated with the same loss of function Bcor alleles show a low contribution to B and T cells and erythrocytes and have kinked and shortened tails, consistent with reduced Brachyury expression. Together these results suggest that Bcor plays a role in differentiation of multiple tissue lineages during early embryonic development.
Wamstad
Joseph Alan
JA
Molecular, Cellular, Developmental Biology and Genetics Graduate Program, University of Minnesota, Minneapolis, Minnesota, USA.
Corcoran
Connie Marie
CM
Keating
Anne Marjorie
AM
Bardwell
Vivian J
VJ
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D018076:DNA, Complementary; D047108:Embryonic Development; D004627:Embryonic Induction; D053595:Embryonic Stem Cells / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008817:Mice, Mutant Strains; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*
C411984:BCOR protein, human; D018076:DNA, Complementary; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins
Exp Hematol. 2005 Jan;33(1):26-34
15661395
Am J Med Genet. 2002 Jul 15;110(4):308-14
12116202
J Embryol Exp Morphol. 1985 Jun;87:27-45
3897439
Genes Dev. 1999 Feb 15;13(4):424-36
10049358
Neurosci Biobehav Rev. 2005 May;29(3):421-30
15820547
Mol Cell Proteomics. 2007 May;6(5):820-34
17296600
Hum Mol Genet. 2007 Jul 15;16(14):1773-82
17517692
Proc Natl Acad Sci U S A. 1981 Dec;78(12):7634-8
6950406
Nature. 1975 Aug 21;256(5519):640-2
1152998
J Exp Zool. 1999 Jun 15;284(1):67-81
10368935
Nat Genet. 1997 Jun;16(2):161-70
9171827
Development. 2001 Jan;128(1):57-65
11092811
Nat Rev Cancer. 2007 Nov;7(11):823-33
17957188
Genes Dev. 2000 Oct 15;14(20):2587-95
11040213
Curr Biol. 1998 May 21;8(11):661-4
9635194
PLoS One. 2007 Jan 17;2(1):e162
17225864
Mol Cell Biol. 1993 Jan;13(1):473-86
8417345
Dev Biol. 1994 Nov;166(1):259-67
7958450
Cell. 1995 Oct 20;83(2):279-87
7585945
Mol Cell Biol. 2002 Oct;22(20):7313-24
12242306
Immunogenetics. 2000 Aug;51(10):788-93
10970093
Leuk Lymphoma. 2003;44 Suppl 3:S5-12
15202519
Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12843-8
16126904
Proc Natl Acad Sci U S A. 2006 May 2;103(18):6946-51
16621925
Mamm Genome. 2000 Mar;11(3):238-40
10723731
J Exp Med. 1997 Aug 4;186(3):439-48
9236196
Nat Rev Genet. 2001 Oct;2(10):743-55
11584291
Gene Expr Patterns. 2007 Apr;7(5):550-7
17344103
Int Rev Immunol. 1999;18(4):381-403
10626250
Cytogenet Genome Res. 2002;99(1-4):210-7
12900566
Genome Res. 2000 Jan;10(1):116-28
10645956
Genes Dev. 1995 Sep 1;9(17):2105-16
7657163
Blood. 1998 Nov 1;92(9):3057-63
9787139
Proc Natl Acad Sci U S A. 1975 Apr;72(4):1441-5
1055416
Endocr Rev. 2007 Aug;28(5):575-87
17609497
Exp Hematol. 2005 Sep;33(9):965-70
16140143
Genes Dev. 1993 Feb;7(2):197-203
8436292
Development. 1991 Jun;112(2):407-15
1794311
Curr Opin Cell Biol. 2007 Jun;19(3):290-7
17481880
Exp Eye Res. 2000 May;70(5):683-92
10870527
Int Immunol. 2007 Apr;19(4):427-33
17307796
Cell. 1998 Oct 30;95(3):379-91
9814708
Genes Dev. 2000 Jul 15;14(14):1810-23
10898795
Curr Opin Cell Biol. 1995 Dec;7(6):862-9
8608017
Pathol Biol (Paris). 2007 Feb;55(1):73-83
16815642
Toxicol Pathol. 2007 Oct;35(6):819-26
17943656
Nat Genet. 2005 Jun;37(6):625-9
15908950
Genes Dev. 2005 May 15;19(10):1129-55
15905405
Int J Oral Maxillofac Surg. 2006 Nov;35(11):1060-2
16829040
Am J Med Genet A. 2003 Dec 15;123A(3):261-6
14608648
Crit Rev Eukaryot Gene Expr. 2005;15(3):207-16
16390317
Methods. 2001 Dec;25(4):402-8
11846609
Science. 1997 Apr 25;276(5312):589-92
9110977
Proc Natl Acad Sci U S A. 1979 Feb;76(2):867-71
284410
Oncogene. 2003 May 29;22(22):3395-406
12776190
Nature. 2006 May 18;441(7091):349-53
16625203
Nat Genet. 2005 Jun;37(6):620-4
15908953
Nat Genet. 2004 Apr;36(4):411-6
15004558
Mol Cell Biol. 2006 Sep;26(18):6880-9
16943429
Cell. 1997 Jun 13;89(6):981-90
9200616
Methods Enzymol. 2003;365:39-59
14696336
Development. 1991 Jun;112(2):397-406
1794310
Anal Biochem. 1978 Apr;85(2):506-18
646104
Methods Enzymol. 2003;365:186-202
14696346