BHLHE40 (basic helix-loop-helix family member e40)

Gene

• Entrez ID: 8553
• Gene name: Basic helix-loop-helix family member e40
• Gene symbol: BHLHE40
• Synonyms: BHLHB2, Clast5, DEC1, HLHB2, SHARP-2, SHARP2, STRA13, Stra14
• Chromosome: 3
• Chromosome location: 3p26.1
• Summary: This gene encodes a basic helix-loop-helix protein expressed in various tissues. The encoded protein can interact with ARNTL or compete for E-box binding sites in the promoter of PER1 and repress CLOCK/ARNTL`s transactivation of PER1. This gene is believed to be involved in the control of circadian rhythm and cell differentiation. [provided by RefSeq, Feb 2014]

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT018020	hsa-miR-335-5p	Microarray	18185580
MIRT036578	hsa-miR-941	CLASH	23622248
MIRT039240	hsa-miR-454-3p	CLASH	23622248
MIRT092209	hsa-miR-15a-5p	HITS-CLIP	22473208
MIRT092210	hsa-miR-16-5p	HITS-CLIP	22473208
MIRT092212	hsa-miR-15b-5p	HITS-CLIP	22473208
MIRT092213	hsa-miR-195-5p	HITS-CLIP	22473208
MIRT092229	hsa-miR-767-3p	HITS-CLIP	23824327
MIRT162881	hsa-miR-374a-5p	HITS-CLIP	22473208
MIRT255697	hsa-miR-345-3p	HITS-CLIP	24906430
MIRT255697	hsa-miR-345-3p	HITS-CLIP	23824327
MIRT255697	hsa-miR-345-3p	HITS-CLIP	19536157
MIRT255697	hsa-miR-345-3p	HITS-CLIP	27418678
MIRT255698	hsa-miR-3140-5p	HITS-CLIP	24906430
MIRT255698	hsa-miR-3140-5p	HITS-CLIP	23824327
MIRT255698	hsa-miR-3140-5p	HITS-CLIP	19536157
MIRT255698	hsa-miR-3140-5p	HITS-CLIP	27418678
MIRT255699	hsa-miR-3620-3p	HITS-CLIP	24906430
MIRT255699	hsa-miR-3620-3p	HITS-CLIP	23824327
MIRT255699	hsa-miR-3620-3p	HITS-CLIP	19536157
MIRT255699	hsa-miR-3620-3p	HITS-CLIP	27418678
MIRT255700	hsa-miR-4686	HITS-CLIP	23824327
MIRT255701	hsa-miR-5187-3p	HITS-CLIP	23824327
MIRT255701	hsa-miR-5187-3p	HITS-CLIP	19536157
MIRT255701	hsa-miR-5187-3p	HITS-CLIP	27418678
MIRT255702	hsa-miR-6828-3p	HITS-CLIP	23824327
MIRT608446	hsa-miR-3941	HITS-CLIP	24906430
MIRT608446	hsa-miR-3941	HITS-CLIP	23824327
MIRT608446	hsa-miR-3941	HITS-CLIP	19536157
MIRT608446	hsa-miR-3941	HITS-CLIP	27418678
MIRT608447	hsa-miR-603	HITS-CLIP	24906430
MIRT608447	hsa-miR-603	HITS-CLIP	23824327
MIRT608447	hsa-miR-603	HITS-CLIP	19536157
MIRT608447	hsa-miR-603	HITS-CLIP	27418678
MIRT608448	hsa-miR-362-3p	HITS-CLIP	24906430
MIRT608448	hsa-miR-362-3p	HITS-CLIP	23824327
MIRT608448	hsa-miR-362-3p	HITS-CLIP	19536157
MIRT608448	hsa-miR-362-3p	HITS-CLIP	27418678
MIRT608449	hsa-miR-329-3p	HITS-CLIP	24906430
MIRT608449	hsa-miR-329-3p	HITS-CLIP	23824327
MIRT608449	hsa-miR-329-3p	HITS-CLIP	19536157
MIRT608449	hsa-miR-329-3p	HITS-CLIP	27418678
MIRT608450	hsa-miR-8485	HITS-CLIP	24906430
MIRT608450	hsa-miR-8485	HITS-CLIP	23824327
MIRT608450	hsa-miR-8485	HITS-CLIP	19536157
MIRT608450	hsa-miR-8485	HITS-CLIP	27418678
MIRT660300	hsa-miR-6749-3p	HITS-CLIP	23824327
MIRT660301	hsa-miR-8059	HITS-CLIP	23824327
MIRT660302	hsa-miR-4471	HITS-CLIP	23824327
MIRT660303	hsa-miR-4469	HITS-CLIP	23824327
MIRT660304	hsa-miR-6784-5p	HITS-CLIP	23824327
MIRT660305	hsa-miR-4667-3p	HITS-CLIP	23824327
MIRT660306	hsa-miR-1470	HITS-CLIP	23824327
MIRT660307	hsa-miR-6764-5p	HITS-CLIP	23824327
MIRT660308	hsa-miR-1915-3p	HITS-CLIP	23824327
MIRT660309	hsa-miR-7113-5p	HITS-CLIP	23824327
MIRT660310	hsa-miR-6822-5p	HITS-CLIP	23824327
MIRT660311	hsa-miR-6750-5p	HITS-CLIP	23824327
MIRT660312	hsa-miR-483-3p	HITS-CLIP	23824327
MIRT677682	hsa-miR-4643	HITS-CLIP	23824327

Transcription factors

Transcription factor	Regulation	Reference
ARNT	Unknown	12354771
ARNTL	Activation	19032342
CLOCK	Activation	19032342
NR1H3	Activation	19032342
VDR	Unknown	23220548
VHL	Unknown	11278694

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	IDA	12397359, 12624110, 14672706, 15193144
GO:0000785	Component	Chromatin	ISA
GO:0000978	Function	RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA	21873635
GO:0000981	Function	DNA-binding transcription factor activity, RNA polymerase II-specific	IBA	21873635
GO:0000981	Function	DNA-binding transcription factor activity, RNA polymerase II-specific	IDA	12397359
GO:0000981	Function	DNA-binding transcription factor activity, RNA polymerase II-specific	ISA
GO:0000981	Function	DNA-binding transcription factor activity, RNA polymerase II-specific	ISS
GO:0001102	Function	RNA polymerase II activating transcription factor binding	ISS
GO:0001227	Function	DNA-binding transcription repressor activity, RNA polymerase II-specific	IDA	12397359, 12624110, 15193144, 18411297, 19786558
GO:0003700	Function	DNA-binding transcription factor activity	NAS	9240428
GO:0005515	Function	Protein binding	IPI	11278694, 12397359, 17347673, 19786558, 22458338, 22723347, 25416956, 25910212, 29234281, 29892012, 31515488, 32296183
GO:0005634	Component	Nucleus	IBA	21873635
GO:0005634	Component	Nucleus	IDA	12624110, 28797635
GO:0005634	Component	Nucleus	NAS	9240428
GO:0005737	Component	Cytoplasm	IEA
GO:0006355	Process	Regulation of transcription, DNA-templated	NAS	9240428
GO:0006357	Process	Regulation of transcription by RNA polymerase II	IBA	21873635
GO:0007623	Process	Circadian rhythm	IDA	28797635
GO:0009952	Process	Anterior/posterior pattern specification	IBA	21873635
GO:0016604	Component	Nuclear body	IDA
GO:0019904	Function	Protein domain specific binding	IPI	15560782
GO:0032922	Process	Circadian regulation of gene expression	IBA	21873635
GO:0032922	Process	Circadian regulation of gene expression	IDA	18411297
GO:0042752	Process	Regulation of circadian rhythm	ISS
GO:0042803	Function	Protein homodimerization activity	IDA	15560782
GO:0043153	Process	Entrainment of circadian clock by photoperiod	ISS	18411297
GO:0043425	Function	BHLH transcription factor binding	IPI	12397359, 15193144
GO:0043426	Function	MRF binding	ISS
GO:0043433	Process	Negative regulation of DNA-binding transcription factor activity	IDA	18411297
GO:0045892	Process	Negative regulation of transcription, DNA-templated	IDA	12397359, 30012868
GO:0045892	Process	Negative regulation of transcription, DNA-templated	IMP	28797635
GO:0046982	Function	Protein heterodimerization activity	IPI	12397359, 15193144, 15560782
GO:0050767	Process	Regulation of neurogenesis	IBA	21873635
GO:0070888	Function	E-box binding	IDA	12397359, 12624110, 14672706, 15193144, 15560782, 18411297, 28797635
GO:1990837	Function	Sequence-specific double-stranded DNA binding	IDA	28473536

Other IDs

• MIM: 604256
• HGNC: 1046
• e!Ensembl: ENSG00000134107

Protein

• UniProt ID: O14503
• Protein name: Class E basic helix-loop-helix protein 40 (bHLHe40) (Class B basic helix-loop-helix protein 2) (bHLHb2) (Differentially expressed in chondrocytes protein 1) (DEC1) (Enhancer-of-split and hairy-related protein 2) (SHARP-2) (Stimulated by retinoic acid gene 13 protein)
• Protein function: Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes (PubMed:12397359, PubMed:18411297). Acts as the negative limb of a novel autoregulatory feedback loop (DEC loop) which differs from the one formed by the PER and CRY transcriptional repressors (PER/CRY loop) (PubMed:14672706). Both these loops are interlocked as it represses the expression of PER1/2 and in turn is repressed by PER1/2 and CRY1/2 (PubMed:15193144). Represses the activity of the circadian transcriptional activator: CLOCK-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer by competing for the binding to E-box elements (5'-CACGTG-3') found within the promoters of its target genes (PubMed:15560782). Negatively regulates its own expression and the expression of DBP and BHLHE41/DEC2 (PubMed:14672706). Acts as a corepressor of RXR and the RXR-LXR heterodimers and represses the ligand-induced RXRA and NR1H3/LXRA transactivation activity (PubMed:19786558). May be involved in the regulation of chondrocyte differentiation via the cAMP pathway (PubMed:19786558). Represses the transcription of NR0B2 and attentuates the transactivation of NR0B2 by the CLOCK-ARNTL/BMAL1 complex (PubMed:28797635). Drives the circadian rhythm of blood pressure through transcriptional repression of ATP1B1 in the cardiovascular system (PubMed:30012868).
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00010	HLH	53 → 108	Helix-loop-helix DNA-binding domain	Domain
  PF07527	Hairy_orange	141 → 180	Hairy Orange	Domain

• Sequence:

  MERIPSAQPPPACLPKAPGLEHGDLPGMYPAHMYQVYKSRRGIKRSEDSKETYKLPHRLI
  EKKRRDRINECIAQLKDLLPEHLKLTTLGHLEKAVVLELTLKHVKALTNLIDQQQQKIIA
  LQSGLQAGELSGRNVETGQEMFCSGFQTCAREVLQYLAKHENTRDLKSSQLVTHLHRVVS
  ELLQGGTSRKPSDPAPKVMDFKEKPSSPAKGSEGPGKNCVPVIQRTFAHSSGEQSGSDTD
  TDSGYGGESEKGDLRSEQPCFKSDHGRRFTMGERIGAIKQESEEPPTKKNRMQLSDDEGH
  FTSSDLISSPFLGPHPHQPPFCLPFYLIPPSATAYLPMLEKCWYPTSVPVLYPGLNASAA
  ALSSFMNPDKISAPLLMPQRLPSPLPAHPSVDSSVLLQALKPIPPLNLETKD

• Sequence length: 412

Pathways

KEGG:

Circadian rhythm

Associated diseases

Disease name	Disease term	References
	Advanced Sleep Phase Syndrome	25395965
	Bipolar Disorder	25395965, 18228528, 20072116
	Depression, Bipolar	25395965
	Delayed Sleep Phase Syndrome	25395965
	Giant Cell Glioblastoma	23582323
	Glioblastoma	23582323
	Glioblastoma Multiforme	23582323
	Hypothyroidism	30595370
	Manic	25395965
	Manic Disorder	25395965
	Myocardial Ischemia	16214533
	Non-24 Hour Sleep-Wake Disorder	25395965
	Nonorganic Sleep Wake Cycle Disorders	25395965
	Schizophrenia	20691775
	Shift-Work Sleep Disorder	25395965