BHLHE41
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Location (UCSC) | Chr 12: 26.12 – 26.13 Mb | Chr 6: 145.8 – 145.81 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
"Basic helix-loop-helix family, member e41", or BHLHE41, is a
History
Structure
BHLHE41 is a member of the DEC subfamily within the basic helix-loop-helix (bHLH) proteins gene family.
The BHLHE41 protein has a myc-type,
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
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,
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] Mice with this mutation sleep less. They get less of both REM and non-REM sleep and recover more easily from sleep deprivation.[10] These effects are not seen in BHLHE41 knockout mice. As such, scholars believe the Dec2-P385R mutation is a dominant negative mutation.[31]
Ying-Hui Fu's lab found this mutation in familial natural short sleepers (FNSS).[8][32][24] FNSS naturally sleep less, about 6-6.5 hours a night.[10] It is not clear how this works. It is possible BHLHE41 makes sleep shorter through pathways independent of those which regulate the molecular core clock, such as the pathway involving the PER2 gene.[10] Both BHLHE41 and PER2 also affect immune function, maybe because tuning the immune system could be one of the reasons we sleep at all.[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
Muscle
BHLHE41 has been shown to repress 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
- ^ a b c GRCh38: Ensembl release 89: ENSG00000123095 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030256 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "BHLHE41 basic helix-loop-helix family, member e41 [ Homo sapiens (human) ]". National Center for Biotechnology Information.
- ^ "Bhlhe41 basic helix-loop-helix family, member e41 [ Mus musculus (house mouse) ]". NCBI.
- PMID 18557763.
- ^ a b c "Entrez Gene: BHLHB3 basic helix-loop-helix domain containing, class B, 3".
- ^ "Basic Helix-Loop-Helix Family, Member E41". Weizmann Institute of Science. Archived from the original on 2014-05-28. Retrieved 2014-05-27.
- ^ PMID 23702243.
- PMID 19881507.
- S2CID 39552567.
- ^ PMID 11162494.
- ^ S2CID 4426418.
- ^ "BHLHE41 Symbol Report | HUGO Gene Nomenclature Committee". www.genenames.org. Retrieved 2017-04-13.
- ^ "Gene: BHLHE41 (ENSG00000123095) - Summary - Homo sapiens - Ensembl genome browser 88". www.ensembl.org. Retrieved 2017-04-13.
- ^ "Transcript: BHLHE41-002 (ENST00000541271.1) - Summary - Homo sapiens - Ensembl genome browser 88". www.ensembl.org. Retrieved 2017-04-13.
- ^ "Transcript: BHLHE41-003 (ENST00000394326.2) - Summary - Homo sapiens - Ensembl genome browser 88". www.ensembl.org. Retrieved 2017-04-13.
- ^ "Transcript: BHLHE41-001 (ENST00000242728.4) - Summary - Homo sapiens - Ensembl genome browser 88". www.ensembl.org. Retrieved 2017-04-13.
- ^ "Gene: BHLHE41 (ENSG00000123095) - Paralogues - Homo sapiens - Ensembl genome browser 88". www.ensembl.org. Retrieved 2017-04-13.
- ^ "ortholog_gene_79365[group] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-04-13.
- ^ "Transcript: BHLHE41-001 (ENST00000242728.4) - Domains & features - Homo sapiens - Ensembl genome browser 88". www.ensembl.org. Retrieved 2017-04-13.
- PMID 15186484.
- ^ PMID 19679812.
- ^ )
- PMID 15465493.
- )
- PMID 27648362.
- PMID 26100875.
- PMID 22849821.
- S2CID 20369654.
- PMID 25083013.
- ^ PMID 27867498.
- ^ PMID 26819638.
- PMID 15970569.
- ^ S2CID 4402132.
- S2CID 36831167.
- 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. S2CID 24030621.
- 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. 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. 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. S2CID 4426418.
- 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. 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. 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. 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.