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
"Basic helix-loop-helix family, member e41", orBHLHE41, is agene that encodes abasic helix-loop-helixtranscription factor repressor protein in various tissues of both humans and mice.[5][6][7][8] It is also known asDEC2,hDEC2, andSHARP1, and was previously known as "basic helix-loop-helix domain containing, class B, 3", orBHLHB3.[9] BHLHE41 is known for its role in thecircadian molecular mechanisms that influence sleep quantity as well as its role in immune function and the maturation ofT helper type 2 cell lineages associated withhumoral immunity.[10][11]
Klaus-Armin Nave's lab identified BHLHE41/SHARP1 andBHLHE40/SHARP2 as a novel subfamily in thebasic helix-loop-helix (BHLH) protein family.[12] They differentiated BHLHE41/SHARP1 and BHLHE40/SHARP2 from other BHLH-protein encodinggenes since they are nottranscribed until the end ofembryonic development. TheDNA sequence of BHLHE41 was first obtained by Dr. Yukia Kato's lab through acDNA library search. Particularly, they obtained the sequence of BHLHE40/DEC1 and conducted anexpressed 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 aregulator in the mammaliancircadian clock.[14] The role of BHLHE41 in other pathways is still being fully characterized.
BHLHE41 is a member of the DEC subfamily within the basic helix-loop-helix (bHLH) proteins gene family.[13][15] BHLHE41 was mapped to humanchromosome 12: 26,120,026-26-125-127 reverse strand and has a total length of 5,101base 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 knownsplice variants. BHLHE41-002[17] and BHLHE41-003[18] are retainedintrons and do not code for a protein. BHLHE41-001 contains 5 codingexons, has a transcript length of 3,837 base pairs, and encodes the 482 amino acid BHLHE41 protein.[19][1] BHLHE40 is theparalogue of BHLHE41.[20] BHLHE41 currently has 165 knownorthologs.[21][2]
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 hasalanine andglycine-rich regions in theC-terminal, and lacks the WRPW motif for interaction with the corepressor Groucho.[13]
BHLHE41 recruits thehistone methyltransferaseG9a and histone deacetylases HDAC1 and Sirt1 to mediate chromatin modifications that repress target gene expression.[25]
BHLHE41 is expressed in thesuprachiasmatic 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 transcriptionalrepressors that function as downstream targets to regulate cell fate during tissue development.[26] BHLHE41 acts as a transcriptional repressor and as aregulator of theCircadian clock.[8] In the clock, the transcriptional factorsClock andBmal form a heterodimer. This heterodimer binds to theE-Boxpromoter element, thereby promoting transcription of downstream genes such asPer and BHLHe41.[27] After transcription and translation, the protein product of BHLHE41 (DEC2) reenters thenucleus and competes with Clock-Bmal1 heterodimer for E-Box element binding (throughcompetitive inhibition); this acts as a suppressor for per gene transcription.[14]
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.
A mutation causingfamilial natural short sleep in one affected family was identified.[24] However, subsequentbiobank research showed that other carriers of this mutation or of different high-impact mutations in the same gene did not exhibit any change in sleep duration, indicating that the cause of the short sleeper phenotype in this family had a different basis.[30]
A mutation causingfamilial natural short sleep in one affected family was identified.[24] However, subsequent research showed that other carriers of this mutation or of different high-impact mutations in the same gene did not exhibit any change in sleep duration, indicating that the cause of the short sleeper phenotype in this family had a different basis.[31]
Thispoint mutation substitutes C to G in DEC2/BHLHE41 DNA sequence results in the substitution ofproline at position 384 witharginine. The proline residue is located close to the C-terminalhistone 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.[32] These effects are not seen in BHLHE41 knockout mice.
BHLHE41knockout mice, also known as BHLHE41 -/- or BHLHE41 null, showed no change in their free-running period with respect to activity. After being exposed to anin vivo model of allergicasthma, BHLHE41 knockout mice show decreasedTH2 cytokine production, defective TH2 responses after being repeatedly stimulated withOVA 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]
BHLHE41 has been shown to beregulator ofT-cell activation. BHLHE41 upregulatesCD25 expression through aStat6-dependent mechanism, which enhances theIL-2 receptor-mediated signal pathway, which promotes TH2 differentiation.Gata3 enhances T helper cell 2 (Th2) differentiation signals by regulating BHLHE41 expression through anautoregulatory loop.[25]
Hypoxia stimulateshypoxia-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 aproteasome complex, which induces HIF-1α'sdegradation.[25]
BHLHE41 and BHLHE40 are transcriptional targets ofSREBP-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 severalcontractile proteins andmitochondrial proteins inskeletal muscle. BHLHE41 and BHLHE40 also repress SREBP-1. This forms anegative feedback loop between SREBP-1, BHLHE40, and BHLHE41 in muscles that runs on a 24-hourcircadian cycle, which has a 12-hour offset between SREBP-1 and BHLHE40/BHLHE41.[33] In addition, BHLHE41 is known to inhibitinflammation andadipogenic differentiation in muscles.[34]
Sarcoma, oral cancer, liver cancer, and colon cancer
BHLHE41 is thought to be a critical regulator of the metastasis oftriple-negative-breast cancer (TNBC).[36] Regulated by the p63 metastasis suppressor, BHLHE41 inhibits TNBC through the inhibition of HIF-1α andhypoxia-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]
^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):460–475.doi:10.1006/mcne.1997.0640.PMID9361282.S2CID39552567.
^abcdFujimoto K, Shen M, Noshiro M, Matsubara K, Shingu S, Honda K, et al. (January 2001). "Molecular cloning and characterization of DEC2, a new member of basic helix-loop-helix proteins".Biochemical and Biophysical Research Communications.280 (1):164–171.doi:10.1006/bbrc.2000.4133.PMID11162494.
^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):707–711.doi:10.1016/j.modgep.2004.04.007.PMID15465493.
^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.110:339–72.doi:10.1016/B978-0-12-405943-6.00010-5.ISBN9780124059436.PMID25248482.
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):535–546.doi:10.1002/1097-0215(20001115)88:4<535::AID-IJC4>3.0.CO;2-V.PMID11058868.S2CID24030621.
