BHLHE41

"Basic helix-loop-helix family, member e41", or BHLHE41, is a gene that encodes a basic helix-loop-helix transcription factor repressor protein in various tissues of both humans and mice.[5][6][7][8] It is also known as DEC2, hDEC2, and SHARP1, and was previously known as "basic helix-loop-helix domain containing, class B, 3", or BHLHB3.[9] BHLHE41 is known for its role in the circadian molecular mechanisms that influence sleep quantity as well as its role in immune function and the maturation of T helper type 2 cell lineages associated with humoral immunity.[10][11]

BHLHE41
Identifiers
Aliases	BHLHE41, DEC2, SHARP1, BHLHe41, HDEC2, SHARP-1, BHLHB3, Basic Helix-Loop-Helix Family Member E41, Basic Helix-Loop-Helix Family, Member E41, Class E Basic Helix-Loop-Helix Protein 41, Class B Basic Helix-Loop-Helix Protein 3, Basic Helix-Loop-Helix Domain Containing, Class B, 3, Differentially Expressed In Chondrocytes 2, Differentially Expressed In Chondrocytes Protein 2, Enhancer-Of-Split And Hairy-Related Protein 1, FNSS1
External IDs	OMIM: 606200 MGI: 1930704 HomoloGene: 137401 GeneCards: BHLHE41
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12p12.1 Start 26,120,030 bp[1] End 26,125,037 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 G3|6 77.7 cM Start 145,858,243 bp[2] End 145,865,558 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • DNA binding • protein dimerization activity • protein homodimerization activity • MRF binding • GO:0001106 transcription corepressor activity • histone deacetylase binding • RNA polymerase II activating transcription factor binding • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • GO:0001078, GO:0001214, GO:0001206 DNA-binding transcription repressor activity, RNA polymerase II-specific • bHLH transcription factor binding • E-box binding • GO:0001948 protein binding • protein heterodimerization activity • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific • RNA polymerase II regulatory region sequence-specific DNA binding • transcription factor binding • sequence-specific DNA binding • sequence-specific double-stranded DNA binding Cellular component • cell nucleus Biological process • cell differentiation • regulation of transcription, DNA-templated • rhythmic process • negative regulation of transcription by competitive promoter binding • negative regulation of transcription from RNA polymerase II promoter • circadian regulation of gene expression • transcription, DNA-templated • negative regulation of myotube differentiation • animal organ morphogenesis • cellular proliferation • negative regulation of transcription, DNA-templated • circadian rhythm • somitogenesis • Notch signaling pathway • regulation of neurogenesis • anterior/posterior pattern specification Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	79365	79362
Ensembl	ENSG00000123095	ENSMUSG00000030256
UniProt	Q9C0J9	Q99PV5
RefSeq (mRNA)	NM_030762	NM_001271768 NM_024469
RefSeq (protein)	NP_110389	NP_001258697 NP_077789
Location (UCSC)	Chr 12: 26.12 – 26.13 Mb	Chr 6: 145.86 – 145.87 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

History

Dr. Klaus-Armin Nave's lab identified BHLHE41/SHARP1 and BHLHE40/SHARP2 as a novel subfamily in the basic helix-loop-helix (BHLH) protein family.[12] They differentiated BHLHE41/SHARP1 and BHLHE/40SHARP2 from other BHLH-protein encoding genes since they are not transcribed until the end of embryonic development. The DNA sequence of BHLHE41 was first obtained by Dr. Yukia Kato's lab through a cDNA library search. Particularly, they obtained the sequence of BHLHE40/DEC1 and conducted an expressed sequence tag (EST) search to identify the BHLHE41/DEC2 sequence. BHLHE41/DEC2 and BHLHE40/DEC1 share 97% homology in the BHLH domain.[13] After the identification of the BHLHE41 gene, Dr. Ken-Ichi Honma's lab characterized its role as a regulator in the mammalian circadian clock.[14] The role of BHLHE41 in other pathways is still being fully characterized.

Structure

BHLHE41 is a member of the DEC subfamily within the basic helix-loop-helix (bHLH) proteins gene family.[13][15] BHLHE41 was mapped to human chromosome 12: 26,120,026-26-125-127 reverse strand and has a total length of 5,101 base pairs.[16] The gene is also mapped to 6 G2-G3 on the mouse chromosome, and 4q43 distal-q4 on the rat chromosome respectively.[13] BHLHE41 has 3 known splice variants. BHLHE41-002[17] and BHLHE41-003[18] are retained introns and do not code for a protein. BHLHE41-001 contains 5 coding exons, has a transcript length of 3,837 base pairs, and encodes the 482 amino acid BHLHE41 protein.[19] BHLHE40 is the paralogue of BHLHE41.[20] BHLHE41 currently has 165 known orthologs.[21]

The BHLHE41 protein has a myc-type, basic helix-loop-helix (bHLH) domain and an orange domain.[22] The orange domain is a 30 residue sequence located on the carboxy-terminal end relative to the BHLH domain of the protein whose function is still unclear.[23] The basic helix-loop-helix domain allows members of the protein family to dimerize with each other to affect gene transcription through binding to specific DNA sequences.[24] BHLHE41 protein also has alanine and glycine-rich regions in the C-terminal, and lacks the WRPW motif for interaction with the corepressor Groucho.[13]

BHLHE41 recruits the histone methyltransferase G9a and histone deacetylases HDAC1 and Sirt1 to mediate chromatin modifications that repress target gene expression.[25]

Function

Circadian

BHLHE41 is expressed in the suprachiasmatic nucleus with levels peaking during subjective day.[14] The gene encodes for a transcription factor that belongs to the Hairy/Enhancer of Split (Hes) subfamily of basic helix-loop-helix factor genes which encode transcriptional repressors that function as downstream targets to regulate cell fate during tissue development.[26] BHLHE41 acts as a transcriptional repressor and as a regulator of the Circadian clock.[8] In the clock, the transcriptional factors Clock and Bmal form a heterodimer. This heterodimer binds to the E-Box promoter element, thereby promoting transcription of downstream genes such as Per and BHLHe41.[27] After transcription and translation, the protein product of BHLHE41 (DEC2) reenters the nucleus and competes with Clock-Bmal1 heterodimer for E-Box element binding (through competitive inhibition); this acts as a suppressor for per gene transcription.[14]

Non-Circadian

BHLHE41 has also been implicated in multiple other pathways. Deregulation of BHLHE41 transcription levels has been characterized as a marker in the progression of several cancers. Low levels of BHLHE41 transcript has been associated with tumor growth suggesting that BHLHE41 suppresses tumor proliferation; however, no definite mechanism of action has been discovered.[28] Dec2 has also been hypothesized to be involved in the regulation of immune responses.[10] Further research on characterizing these pathways and BHLHE41's specific role is still being conducted.

In mice lacking SHARP1/BHLHE41 and SHARP2, IGF-2 is elevated and leads to enhanced memory consolidation.[29]

Mutations

There is a known amino acid point mutation of DEC2 that affects the regulation of the biological processes of sleep timing and duration in humans.[10] Although the exact mechanisms of action are still unknown, previous studies suggest that the mutation poses similar effects in both humans and mice.[10]

DEC2-P385R

A point mutation substituting C to G in DEC2/BHLHE41 DNA sequence results in the substitution of proline at position 385 with arginine. The proline at position 385 (384 according to the talk page) of BHLHE41 is located close to the C-terminal histone deacetylase-interacting region of BHLHE41, which is a highly conserved region within the proline-rich domain.[24] This mutation mitigates BHLHe41's transcriptional inhibitory function.[30] Furthermore, mice with this mutation show aberrations in sleep homeostasis as they undergo a shorter duration of REM and non-REM sleep and recover more readily from sleep deprivation.[10] Since these effects are not seen in BHLHE41 knockout mice, it is believed that the Dec2-P385R mutation is a dominant negative mutation.[31]

Ying-Hui Fu's lab implicated this mutation in people afflicted with Familial Natural Short Sleepers (FNSS).[8][32][24] Individuals characterized with Familial Natural Short Sleepers (FNSS) have a condition which causes them to naturally sleep an average of 6-6.5 hours a night; they have the natural short sleeper phenotype (NSS).[10] Although the exact mechanism through which this mutation functions is still unknown, findings suggest that BHLHE41 alters sleep duration through pathways independent of those which regulate the molecular core clock, such as the pathway involving the PER2 gene.[10] In addition, both BHLHE41 and PER2 also influence immune function, which recent studies have suggested may be important in regulating a potentially important role of sleep.[10]

BHLHE41 Knockout

BHLHE41 knockout mice, also known as BHLHE41 -/- or BHLHE41 null, showed no change in their free-running period with respect to activity. After being exposed to an in vivo model of allergic asthma, BHLHE41 knockout mice show decreased TH2 cytokine production, defective TH2 responses after being repeatedly stimulated with OVA peptide, and reduced alveolar infiltrate.[10] BHLHE41 knockout mice had increased post-natal regeneration of muscle after injury. However, these mice showed no deficits in embryonic muscle repair.[33]

Clinical significance

Immune System

BHLHE41 has been shown to be regulator of T-cell activation. BHLHE41 upregulates CD25 expression through a Stat6-dependent mechanism, which enhances the IL-2 receptor-mediated signal pathway, which promotes TH2 differentiation. Gata3 enhances T helper cell 2 (Th2) differentiation signals by regulating BHLHE41 expression through an autoregulatory loop.[25]

Hypoxia

Hypoxia stimulates hypoxia-inducible factor-1 alpha (HIF-1α) to be produced, which initiates the hypoxic response. HIF-1α induces the transcription of BHLHE41 and BHLHE40. This is believed to repress cell proliferation, which is not conducive to a hypoxic environment.[33] BHLHE41 can also block a hypoxic response by presenting HIF-1α to a proteasome complex, which induces HIF-1α's degradation.[25]

Muscle

BHLHE41 has been shown to represses myogenic differentiation by inhibiting MyoD activity through multiple mechanisms. When BHLHE41 dimerizes with MyoD and E47, it prevents the formation of MyoD-E47 heterodimers, which are functional. When BHLHE41 is sumoylated at K240 and K255, it recruits the histone methyltransferase G9a. G9a then catalyzes repressive histone 3 lysine 9 dimethylation (H3K9me2) at promoter sites of target genes of MyoD. G9a also methylates MyoD, which inhibits MyoD's transcriptional activity.[25]

BHLHE41 and BHLHE40 are transcriptional targets of SREBP-1 (also known as ADD-1) isoforms SREBP-1a and SREBP-1c. After being induced by SREBP-1, BHLHE41 and BHLHE40 have been shown to repress myogenesis by blocking MYOD1 transcription. BHLHE40 and BHLHE41 are also known to alter the expression of several contractile proteins and mitochondrial proteins in skeletal muscle. BHLHE41 and BHLHE40 also repress SREBP-1. This forms a negative feedback loop between SREBP-1, BHLHE40, and BHLHE41 in muscles that runs on a 24-hour circadian cycle, which has a 12-hour offset between SREBP-1 and BHLHE40/BHLHE41.[33] In addition, BHLHE41 is known to inhibit inflammation and adipogenic differentiation in muscles.[34]

Sarcoma, Oral Cancer, Liver Cancer, and Colon Cancer

BHLHE41 has been shown to suppress the expression of vascular endothelial growth factor (VEGF) in sarcoma cells and oral cancer cells. BHLHE41 also suppresses cytochrome P450 2D6 (CYP2D6) in hepatocellular carcinoma cells. While BHLHE40 induces apoptosis, senescence, and epithelial-mesenchymal transition (EMT) in tumor cells, BHLHE41 shows a circadian expression and inhibits EMT, apoptosis, and metastasis in sarcoma cells and hepatocellular carcinoma cells.[34] It has been shown that the normal tissue adjacent to colon carcinomas show high levels of BHLHE41 expression.[35] Research is currently examining whether BHLHE40 and BHLHE41 can be used as target genes for chemotherapy.[34]

Breast Cancer

BHLHE41 is thought to be a critical regulator of the metastasis of triple-negative-breast cancer (TNBC).[36] Regulated by the p63 metastasis suppressor, BHLHE41 inhibits TNBC through the inhibition of HIF-1α and hypoxia-inducible factor 2α (HIF-2α).[36] Studies have shown that BHLHE41 is both required and sufficient to limit the expression of HIF-target genes, by mechanistically binding to HIFs and promoting proteasomal degradation.[36] Breast cancer tumors that show high expression of BHLHE41 and CyclinG2 are believed to have a lower metastatic risk.[37][38]

References

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2. GRCm38: Ensembl release 89: ENSMUSG00000030256 - Ensembl, May 2017
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8. "Entrez Gene: BHLHB3 basic helix-loop-helix domain containing, class B, 3".
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12. Rossner MJ, Dörr J, Gass P, Schwab MH, Nave KA (1997). "SHARPs: mammalian enhancer-of-split- and hairy-related proteins coupled to neuronal stimulation". Molecular and Cellular Neurosciences. 9 (5–6): 460–75. doi:10.1006/mcne.1997.0640. PMID 9361282.
13. Fujimoto K, Shen M, Noshiro M, Matsubara K, Shingu S, Honda K, Yoshida E, Suardita K, Matsuda Y, Kato Y (January 2001). "Molecular cloning and characterization of DEC2, a new member of basic helix-loop-helix proteins". Biochemical and Biophysical Research Communications. 280 (1): 164–71. doi:10.1006/bbrc.2000.4133. PMID 11162494.
14. Honma S, Kawamoto T, Takagi Y, Fujimoto K, Sato F, Noshiro M, Kato Y, Honma K (October 2002). "Dec1 and Dec2 are regulators of the mammalian molecular clock". Nature. 419 (6909): 841–4. doi:10.1038/nature01123. PMID 12397359.
15. "BHLHE41 Symbol Report | HUGO Gene Nomenclature Committee". www.genenames.org. Retrieved 2017-04-13.
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21. "ortholog_gene_79365[group] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-04-13.
22. "Transcript: BHLHE41-001 (ENST00000242728.4) - Domains & features - Homo sapiens - Ensembl genome browser 88". www.ensembl.org. Retrieved 2017-04-13.
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24. He Y, Jones CR, Fujiki N, Xu Y, Guo B, Holder JL, Rossner MJ, Nishino S, Fu YH (August 2009). "The transcriptional repressor DEC2 regulates sleep length in mammals". Science. 325 (5942): 866–70. doi:10.1126/science.1174443. PMC 2884988. PMID 19679812.
25. Ow JR, Tan YH, Jin Y, Bahirvani AG, Taneja R (2014). Stra13 and Sharp-1, the non-grouchy regulators of development and disease. Current Topics in Developmental Biology. bHLH Transcription Factors in Development and Disease. 110. pp. 317–38. doi:10.1016/B978-0-12-405943-6.00009-9. ISBN 9780124059436. PMID 25248481.
26. Piscione TD, Wu MY, Quaggin SE (October 2004). "Expression of Hairy/Enhancer of Split genes, Hes1 and Hes5, during murine nephron morphogenesis". Gene Expression Patterns. 4 (6): 707–11. doi:10.1016/j.modgep.2004.04.007. PMID 15465493.
27. Kato Y, Kawamoto T, Fujimoto K, Noshiro M (2014). DEC1/STRA13/SHARP2 and DEC2/SHARP1 coordinate physiological processes, including circadian rhythms in response to environmental stimuli. Current Topics in Developmental Biology. 110. pp. 339–72. doi:10.1016/B978-0-12-405943-6.00010-5. ISBN 9780124059436. PMID 25248482.
28. Li P, Jia YF, Ma XL, Zheng Y, Kong Y, Zhang Y, Zong S, Chen ZT, Wang YS (2016). "DEC2 suppresses tumor proliferation and metastasis by regulating ERK/NF-κB pathway in gastric cancer". American Journal of Cancer Research. 6 (8): 1741–57. PMC 5004076. PMID 27648362.
29. Shahmoradi A, Radyushkin K, Rossner MJ (July 2015). "Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex". Proceedings of the National Academy of Sciences of the United States of America. 112 (27): E3582–9. doi:10.1073/pnas.1423989112. PMC 4500222. PMID 26100875.
30. Jones CR, Huang AL, Ptáček LJ, Fu YH (May 2013). "Genetic basis of human circadian rhythm disorders". Experimental Neurology. Circadian rhythms and sleep disorders. 243: 28–33. doi:10.1016/j.expneurol.2012.07.012. PMC 3514403. PMID 22849821.
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32. Pellegrino R, Kavakli IH, Goel N, Cardinale CJ, Dinges DF, Kuna ST, Maislin G, Van Dongen HP, Tufik S, Hogenesch JB, Hakonarson H, Pack AI (August 2014). "A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans". Sleep. 37 (8): 1327–36. doi:10.5665/sleep.3924. PMC 4096202. PMID 25083013.
33. Gorski JP, Price JL (2016). "Bone muscle crosstalk targets muscle regeneration pathway regulated by core circadian transcriptional repressors DEC1 and DEC2". BoneKEy Reports. 5: 850. doi:10.1038/bonekey.2016.80. PMC 5111231. PMID 27867498.
34. Sato F, Bhawal UK, Yoshimura T, Muragaki Y (2016). "DEC1 and DEC2 Crosstalk between Circadian Rhythm and Tumor Progression". Journal of Cancer. 7 (2): 153–9. doi:10.7150/jca.13748. PMC 4716847. PMID 26819638.
35. Yamada K, Miyamoto K (September 2005). "Basic helix-loop-helix transcription factors, BHLHB2 and BHLHB3; their gene expressions are regulated by multiple extracellular stimuli". Frontiers in Bioscience. 10 (1–3): 3151–71. doi:10.2741/1772. PMID 15970569.
36. Montagner M, Enzo E, Forcato M, Zanconato F, Parenti A, Rampazzo E, Basso G, Leo G, Rosato A, Bicciato S, Cordenonsi M, Piccolo S (July 2012). "SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors". Nature. 487 (7407): 380–4. doi:10.1038/nature11207. PMID 22801492.
37. Noshiro M, Kawamoto T, Furukawa M, Fujimoto K, Yoshida Y, Sasabe E, Tsutsumi S, Hamada T, Honma S, Honma K, Kato Y (April 2004). "Rhythmic expression of DEC1 and DEC2 in peripheral tissues: DEC2 is a potent suppressor for hepatic cytochrome P450s opposing DBP". Genes to Cells. 9 (4): 317–29. doi:10.1111/j.1356-9597.2004.00722.x. PMID 15066123.
38. Piccolo S, Enzo E, Montagner M (August 2013). "p63, Sharp1, and HIFs: master regulators of metastasis in triple-negative breast cancer". Cancer Research. 73 (16): 4978–81. doi:10.1158/0008-5472.CAN-13-0962. PMID 23913939.

Further reading

• Grottke C, Mantwill K, Dietel M, Schadendorf D, Lage H (November 2000). "Identification of differentially expressed genes in human melanoma cells with acquired resistance to various antineoplastic drugs". International Journal of Cancer. 88 (4): 535–46. doi:10.1002/1097-0215(20001115)88:4<535::AID-IJC4>3.0.CO;2-V. PMID 11058868.
• Garriga-Canut M, Roopra A, Buckley NJ (May 2001). "The basic helix-loop-helix protein, sharp-1, represses transcription by a histone deacetylase-dependent and histone deacetylase-independent mechanism". The Journal of Biological Chemistry. 276 (18): 14821–8. doi:10.1074/jbc.M011619200. PMID 11278948.
• Miyazaki K, Kawamoto T, Tanimoto K, Nishiyama M, Honda H, Kato Y (December 2002). "Identification of functional hypoxia response elements in the promoter region of the DEC1 and DEC2 genes". The Journal of Biological Chemistry. 277 (49): 47014–21. doi:10.1074/jbc.M204938200. PMID 12354771.
• Honma S, Kawamoto T, Takagi Y, Fujimoto K, Sato F, Noshiro M, Kato Y, Honma K (October 2002). "Dec1 and Dec2 are regulators of the mammalian molecular clock". Nature. 419 (6909): 841–4. doi:10.1038/nature01123. PMID 12397359.
• Li Y, Xie M, Song X, Gragen S, Sachdeva K, Wan Y, Yan B (May 2003). "DEC1 negatively regulates the expression of DEC2 through binding to the E-box in the proximal promoter". The Journal of Biological Chemistry. 278 (19): 16899–907. doi:10.1074/jbc.M300596200. PMID 12624110.
• Azmi S, Sun H, Ozog A, Taneja R (May 2003). "mSharp-1/DEC2, a basic helix-loop-helix protein functions as a transcriptional repressor of E box activity and Stra13 expression". The Journal of Biological Chemistry. 278 (22): 20098–109. doi:10.1074/jbc.M210427200. PMID 12657651.
• Oswald F, Winkler M, Cao Y, Astrahantseff K, Bourteele S, Knöchel W, Borggrefe T (December 2005). "RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes". Molecular and Cellular Biology. 25 (23): 10379–90. doi:10.1128/MCB.25.23.10379-10390.2005. PMC 1291242. PMID 16287852.

External links

• Human BHLHE41 genome location and BHLHE41 gene details page in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.