title: The bromodomain-containing gene BRD2 is regulated at transcription, splicing, and translation levels.
abstract: The human BRD2 gene has been linked and associated with a form of common epilepsy and electroencephalographic abnormalities. Disruption of Brd2 in the mouse revealed that it is essential for embryonic neural development and that viable Brd2(+/-) heterozygotes show both decreased GABAergic neuron counts and increased susceptibility to seizures. To understand the molecular mechanisms by which mis-expression of BRD2 might contribute to epilepsy, we examined its regulation at multiple levels. We discovered that BRD2 expresses distinct tissue-specific transcripts that originate from different promoters and have strikingly different lengths of 5' untranslated regions (5'UTR). We also experimentally confirmed the presence of a highly conserved, alternatively spliced exon, inclusion of which would result in a premature termination of translation. Downstream of this alternative exon is a polymorphic microsatellite (GT-repeats). Manipulation of the number of the GT-repeats revealed that the length of the GT-repeats affects the ratio of the two alternative splicing products. In vitro translation and expression in cultured cells revealed that among the four different mRNAs (long and short 5'UTR combined with regular and alternative splicing), only the regularly spliced mRNA with the short 5'UTR yields full-length protein. In situ hybridization and immunohistochemical studies showed that although Brd2 mRNA is expressed in both the hippocampus and cerebellum, Brd2 protein only can be detected in the cerebellar Purkinje cells and not in hippocampal cells. These multiple levels of regulation would likely affect the production of functional BRD2 protein during neural development and hence, its role in the etiology of seizure susceptibility.
authors: Division of Statistical Genetics, Department of Biostatistics, Mailman School of Public Health, Columbia University Medical Center, New York, New York 10032, USA.
authors: Enyuan
authors: E
authors: Shang
authors: Qingping
authors: Q
authors: Cui
authors: Xiangyuan
authors: X
authors: Wang
authors: Cheryl
authors: C
authors: Beseler
authors: David A
authors: DA
authors: Greenberg
authors: Debra J
authors: DJ
authors: Wolgemuth
references: Neurosci Lett. 2006 May 29;400(1-2):135-9
references: 16516380
references: Neurology. 1991 Oct;41(10):1651-5
references: 1922810
references: Mol Cell Biol. 2002 Jun;22(11):3794-802
references: 11997514
references: Science. 2003 Nov 14;302(5648):1212-5
references: 14615540
references: Nat Rev Genet. 2007 Jun;8(6):424-36
references: 17486122
references: Development. 1997 Jun;124(11):2167-77
references: 9187143
references: Oncogene. 1999 Nov 25;18(50):7026-33
references: 10597303
references: Nature. 2007 Feb 8;445(7128):666-70
references: 17237763
references: Dev Dyn. 2009 Apr;238(4):908-17
references: 19301389
references: Eur J Biochem. 2001 Feb;268(4):1076-83
references: 11179974
references: Mol Cell Biol. 1997 Jun;17(6):3194-201
references: 9154818
references: J Biol Chem. 2007 Aug 17;282(33):24343-51
references: 17565985
references: J Cell Sci. 2007 Aug 15;120(Pt 16):2755-61
references: 17690303
references: Genes Dev. 2003 Feb 15;17(4):419-37
references: 12600935
references: Pharmacogenetics. 2000 Mar;10(2):133-40
references: 10762001
references: Am J Hum Genet. 2000 Feb;66(2):508-16
references: 10677311
references: Nat Rev Mol Cell Biol. 2009 Nov;10(11):741-54
references: 19773805
references: Biochim Biophys Acta. 2009 May;1789(5):413-21
references: 19362612
references: Ann Neurol. 2005 Jun;57(6):866-73
references: 15929039
references: J Biol Chem. 2000 Jul 14;275(28):21041-7
references: 10766763
references: EMBO J. 2005 Apr 20;24(8):1608-20
references: 15933722
references: Am J Hum Genet. 1995 May;56(5):1140-6
references: 7726170
references: Curr Opin Cell Biol. 2008 Jun;20(3):253-9
references: 18436437
references: Proc Natl Acad Sci U S A. 2010 May 11;107(19):8824-9
references: 20421462
references: Endocrinology. 1999 Jun;140(6):2790-800
references: 10342870
references: Genes Dev. 2007 Jan 15;21(2):175-83
references: 17234883
references: Front Biosci. 2001 Aug 01;6:D1008-18
references: 11487468
references: Mol Reprod Dev. 1992 Nov;33(3):259-69
references: 1280449
references: Nature. 2011 May 5;473(7345):43-9
references: 21441907
references: Epilepsia. 2007 Apr;48(4):706-12
references: 17437413
references: J Cell Sci. 1998 Dec;111 ( Pt 23):3541-50
references: 9811568
references: Am J Hum Genet. 2003 Aug;73(2):261-70
references: 12830434
references: Am J Med Genet. 1988 Sep;31(1):185-92
references: 3146924
references: Development. 2007 Oct;134(19):3507-15
references: 17728347
references: Genomics. 1998 Jul 1;51(1):114-23
references: 9693039
references: Anal Biochem. 1987 Apr;162(1):156-9
references: 2440339