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FLASH GENE

Symbol

DNMT3B

contributors: mct/npt/pgu - updated : 01-06-2016

HGNC name	DNA (cytosine-5-)-methyltransferase 3 beta
HGNC id	2979

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	46.97 kb     23 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
text structure	at least two TSPs (transcriptional start points ) which exist in different exons and the expression is controlled by different promoters (lacking typical TATA sequences, where one promoter contains a CpG-rich area near the TSP, the other promoter is CpG-poor)

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

text	with at least two alternatively spliced isoforms

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_006892 23 splicing 4353 NP_008823 - 853 ubiquitous except brain, muscle 2004 15148359 NM_175848 22 splicing 4293 NP_787044 - 833 - 2004 15148359 NM_175849 20 splicing 4104 NP_787045 - 770 - 2004 15148359 lacking exon 22-21 capable of DNA binding and contributing factor of DNA methylation variant DNMT3B4 22 splicing - isoform DNMT3B4 - - ubiquitous except brain, lung, prostate, muscle 2004 15148359 lacking exon 21 variant DNMT3B5 22 splicing - isoform DNMT3B5 - - testis (very low), brain, prostate 2004 15148359 lacking exon 22 NM_175850 22 splicing 4267 NP_787046 94.6 845 - 2004 15148359 NM_001207056 - - 3876 - 694 - 2004 15148359 NM_001207055 - - 3978 - 728 - 2004 15148359 DNMT3Bpsc - - - - - expressed in pluripotent stem cells 2011 21698279 alternatively spliced exon 10 isoform is characteristic of the pluripotent state DNMT3B3Delta5 - - - - - - 2009 19825994 lacking exon 5 within the N-terminal regulatory domain possessed significantly enhanced DNA binding affinity and displayed an altered nuclear distribution may play an important role in stem cell maintenance or differentiation and suggest that sequences encoded by exon 5 influence the functional properties of DNMT3B

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 blood / hematopoietic spleen           thymus         Digestive intestine large intestine colon       liver         Nervous brain         Reproductive male system testis

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Lymphoid

cell lineage	abundantly in ES cells, barely detectable in differentiated cells
cell lines
fluid/secretion

at STAGE

physiological period

embryo, fetal, pregnancy

Text	liver, heart, kidney, placenta
	highly expressed during early embryonic development and down-regulated in most differentiated somatic cells

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N terminal PWWP domain central cysteine-rich region with homology with ATRX (XNP)
	a PHD domain
	five C terminal conserved catalytic domains functioning in the transmethylation reaction
	a long N-terminal regulatory region linked to a conserved C-terminal domain responsible for the catalytic activity with a PWWP domain in the N-terminal region, chromatin/chromosome-targeting module essential for the chromatin targeting of the enzymes

HOMOLOGY

interspecies

homolog to murine Dnmt3b

Homologene

FAMILY

C5 (cytosine-5) methyltransferase family

CATEGORY

enzyme , DNA associated

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,chromatin/chromosome,nucleosome
	intracellular,nucleus,chromatin/chromosome,heterochromosome
	intracellular,nucleus,chromatin/chromosome,centromere
text	co-localizing with condensin and KIF4A on condensed chromosomes throughout mitosis
	localizes to both centromeric and pericentromeric regions
	almost all of the cellular contents of DNMT3A/3B, but not DNMT1, are strongly anchored to a subset of nucleosomes

basic FUNCTION	essential for de novo DNA methylation and development (at least in mouse) and catalytically methylating cytosines in CpG pairs
	functions as a co-repressor of polycomb protein in inducing transcriptional repression independent of DNA methylation
	playing a role in chromosome condensation machinery
	plays a critical role in chromosomal stability and maintenance of peri-/centromeric region chromatin structure
	DNMT3A and DNMT3B, but not the maintenance enzyme DNMT1, are redox-dependent DNA dehydroxymethylase
	DNA dehydroxymethylation by DNMT3A, DNMT3B provides a simpler pathway to reduce DNA hydroxymethylation and methylation
	DNMT3A, DNMT3B, DNMT1 roles in Ca(2+) ion-dependent biological processes, including the genome-wide/local DNA demethylation during early embryogenesis, cell differentiation, neuronal activity-regulated gene expression, and carcinogenesis
	DNMT3A and DNMT3B have overlapping and distinct functions in hematopoietic stem cells
	DNMT3A and DNMT3B are critical to regulate the onset of IGK light chain rearrangement during early B-cell development
	DNMT3A and DNMT3B are primarily responsible for de novo methylation of specific cytosine residues in CpG dinucleotides during mammalian development
	subtelomeric DNA undergoes methylation during development by DNMT3B, including the CpG-rich promoters of the long non-coding RNA (TERRA) embedded in these regions

CELLULAR PROCESS

nucleotide

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

signaling

a component	universal repressor complex containing DNMT3B and
	ZHX1

INTERACTION

DNA

RNA

small molecule

protein	HDAC
	interacting with HDAC1, HDAC2, HP1 proteins, SUV39H1, and components of the histone methylation system, the ATP-dependent chromatin remodeling enzyme SMARCA5
	interacting with DNMT3L (stimulating the catalytic activity of DNMT3)
	interacting with CBX4 through its N-terminal regulatory domain
	interaction between DNMT3B and constitutive centromere protein CENPC1, itself essential for mitosis
	link between DNMT3B and centromere dynamics, suggesting that CENPC1 and DNMT3B mutually reinforce each other's recruitment and play a significant role in regulating epigenetic marks at the centromere
	HOXB3 binds to DNMT3B and increases its expression and in turn, is recruited to the RASSF1A promoter, resulting in hypermethylation and silencing of RASSF1A expression (
	TCL1A physically interacts with DNA methylthansferases DNMT3A and DNMT3B
	ability of HELLS to bind ATP and the cellular concentration of DNMT3B are critical for cell-autonomous de novo DNA methylation in somatic cells
	ZBTB24 is a transcriptional regulator that coordinates with DNMT3B to control DNA methylation

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

ICF

related resource

DNMT3Bbase: Mutation registry for ICF syndrome

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   DNMT3B isoform 4 is overexpressed in hepatocellular carcinoma (hypomethylation) tumoral       gain of function in leukemia tumoral         DeltaDNMT3B is the major expression form of DNMT3B in NSCLC tumoral     --over   overexpression was identified as an independent prognostic factor for predicting shortened survival of patients with diffuse large B-cell lymphomas tumoral   amplification     in pancreatic and breast cancer, and is associated with increased resistance to the growth-inhibitory effect mediated by DNA demethylating agents constitutional germinal mutation       heterozygous DNMT3B mutations, only when combined with smaller D4Z4 repeat arrays, can derepress DUX4 in somatic cells and cause FSHMD1a or FSHD2 constitutional       loss of function disruption of DNMT3A or DNMT3B individually as well as of both enzymes in tandem results in viable, pluripotent cell lines with distinct effects on the DNA methylation landscape

Susceptibility

to hereditary nonpolyposis colorectal cancer

Variant & Polymorphism other	polymorphisms associated to nonpolyposis colorectal cancer with early age of onset

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS