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FLASH GENE

Symbol

BRD2

contributors: mct - updated : 23-10-2019

HGNC name	bromodomain containing 2
HGNC id	1103

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	EJM3 myoclonic epilepsy, juvenile, 3
Location	6p21.32      Physical location : 4.168.580 - 32.949.281
Synonym name	female sterile homeotic-related gene 1
	really interesting new gene 3
Synonym symbol(s)	NAT, RNF3, FSRG1, RING3, D6S113E, KIAA9001, DKFZp686N0336, FLJ31942,

DNA

TYPE	functioning gene
STRUCTURE	12.85 kb     13 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	cytosine-phosphate-guanine/HTF
text structure	a CpG island
	DNA demethylation of the BRD2 promoter region induced BRD2 expression during differentiation of 3T3-L1 cells into adipocytes

MAPPING

cloned

Y

linked

N

status

provisional

regionally located

. located to the major histocompatibility complex (MHC) class II region, between HLA-DMA

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005104 13 - 4907 - 801 - 1997 9373153 NM_001113182 13 - 4807 - 801 - 1997 9373153 NM_001199455 13 - 4602 NP_001186384 - 836 - 1997 9373153 NM_001199456 12 - 3210 NP_001186385 - 754 - 1997 9373153 NM_001291986 14 - 4853 NP_001278915 - 681 - 1997 9373153

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Endocrine pancreas       highly Homo sapiens   thyroid       highly Lymphoid/Immune spleen       highly   thymus       highly Nervous brain limbic system hippocampus   highly Homo sapiens BRD2 mRNA   brain hindbrain cerebellum     Homo sapiens BRD2 mRNA Reproductive male system testis

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial barrier/lining

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell Endocrine islet cell (alpha,beta...) Homo sapiens Skin/Tegument keratinocyte

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	highest expression of Brd2 is detected in the developing neural tube

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	common domain architecture featuring two N-terminal bromodomains that exhibit high levels of sequence conservation (inhibitor JQ1 binds to the Kac binding site of BET bromodomains), a dual bromodomains
	an extraterminal domain
	BRD2-BD1 recognizes the H4 tail acetylated at Lys-12 (H4K12ac)
	a PEST domain
	one ET domain
	a RING finger motif
	a more divergent C-terminal recruitment domain, that is important for chromatin interaction and regulation of transcription and alternative splicing

HOMOLOGY

interspecies	homolog to murine Rnf3
	homolog to Drosophila Fsh

intraspecies

paralog to BRD3 (52 p100)

Homologene

FAMILY

bromodomain and extra-terminal (BET) family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
	intracellular,nucleus,chromatin/chromosome
text	mainly localizes in nucleus in two distribution patterns, diffused and dotted

basic FUNCTION	protein serine/threonine kinase, identified by the monoclonal antibody LY9, overexpressed in proliferating endothelial cells
	mitogen-activated kinase
	translocating in the nucleus the promoter of a number of the E2 family of transcription factors
	playing a role in regulating brain development
	having distinct roles in initiating apoptosis, and the dotted distribution pattern in nucleus may be a morphologic marker of cell apoptosis
	TBP-associated protein recruiting TBP into E2F1 transcriptional complex in response to serum stimulation
	has intrinsic histone chaperone activity and is required for transcription of the cyclin D1 gene
	required for the completion of embryogenesis and proper neural tube closure during development
	transcriptional co-activator/co-repressor with SWI/SNF (switch mating type/sucrose non-fermenting)-like functions that regulates chromatin
	BET family members have been recognized as essential genes for the replication of viruses and in mediating inflammatory responses
	BET family proteins recognize acetylated chromatin through their two bromodomains, acting as transcriptional activators or tethering viral genomes to the mitotic chromosomes of their host
	BRD2 is likely required for cell cycle exit and neuronal differentiation of neuroepithelial cells through the E2F1 pathway during CNS development
	BRD2, BRD3, BRD4, and BRDT are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression
	transcriptional coregulator, that couples chromatin to cell-cycle progression
	plays a critical, independent role in regulation of mitogenic response genes, particularly cyclin A, in B cells
	suppresses adipocyte differentiation
	antagonistic relationship between H2AZ1 monoubiquitylated and BRD2 to regulate the transcriptional balance at bivalent genes to enable proper execution of developmental programs
	separate and interdependent BRD2 and BRD4 functions in potentiating the genetic program required for Th17 cell development and adaptive immunity
	BRD2 therefore creates a restricted chromatin environment surrounding DSBs which facilitates DSB repair and which is framed by extensive ZMYND8 domains on the flanking chromatin

CELLULAR PROCESS	cell life, cell death/apoptosis
	nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

development , reproduction/sex

text	spermatogenesis

PATHWAY

metabolism

signaling

signal transduction

signal transduction pathway involved in growth control

a component

INTERACTION

DNA

binding

RNA

small molecule	metal binding,
	Zn2+

protein	interacting with BRD7
	is specifically localized at promoters of target genes, and BRD2 interaction with chromatin cannot be explained solely by histone acetylation
	PTN antagonized the cell-cycle-stimulating activity associated with BRD2, thus enhancing induced neuronal differentiation
	DNA methylation contributes to the regulation of BRD2 expression during pre-adipocyte differentiation (pMID: 25575605)
	is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation
	CTCF recruits BRD2 to co-bound sites whereas BRD2 is dispensable for CTCF occupancy and BRD2 cooperates with CTCF to enforce transcriptional and architectural boundaries
	BRD2 facilitates recruitment of a second bromodomain protein, ZMYND8, which spreads along the flanking chromatin, but is excluded from the DNA double-strand breaks region

cell & other

interacts with acetylated chromatin during mitosis and leads to transcriptional activation in culture cells

REGULATION

inhibited by

JQ1, a selective and potent inhibitor of BET family bromodomains

Other	increased by VPF/VGEF165
	regulated at transcription, splicing, and translation levels

ASSOCIATED DISORDERS

corresponding disease(s)

EJM3

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in certain types of leukemia

Susceptibility

to juvenile myoclonic epilepsy

Variant & Polymorphism SNP , other	polymorphisms confering increased risk of juvenile myoclonic epilepsy

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer     inhibition of the BET-histone interaction results in transcriptional downregulation of a number of oncogenes, providing a novel pharmacologic strategy for the treatment of cancer

ANIMAL & CELL MODELS

	disruption of Brd2, an unusual MHC gene, causes lifelong severe obesity in mice with pancreatic islet expansion, hyperinsulinaemia, hepatosteatosis and elevated pro-inflammatory cytokines, but, surprisingly, enhanced glucose tolerance, elevated adiponectin, increased weight of brown adipose tissue
	viable Brd2(+/-) heterozygotes mice show both decreased GABAergic neuron counts and increased susceptibility to seizures