Alternative titles; symbols
HGNC Approved Gene Symbol: HES1
Cytogenetic location: 3q29 Genomic coordinates (GRCh38): 3:194,136,148-194,138,732 (from NCBI)
HES1 belongs to a family of basic helix-loop-helix (bHLH) proteins that are essential for neurogenesis, myogenesis, hematopoiesis, and sex determination. HES1 is a transcriptional repressor for a number of genes, but it can also function as a transcriptional activator (Yan et al., 2002).
The 'hairy' gene in Drosophila encodes a bHLH protein that functions in at least 2 steps during Drosophila development: first, during embryogenesis, when it partakes in the establishment of segments, and second, during the larval stage, when it functions negatively in determining the pattern of sensory bristles on the adult fly. Feder et al. (1994) reported the genomic cloning of the human hairy gene homolog, HES1, which they called HRY. The predicted amino acid sequence revealed only 4 amino acid differences between the human and rat genes.
By site-directed mutagenesis and overexpression of HRY in human fibroblasts, Yan et al. (2002) showed that HRY, as well as YY1 (600013), functions as a transcriptional activator of acid alpha-glucosidase (GAA; 606800). Using gel shift assays, they found that HRY binds to a 25-bp enhancer element within the first intron of the GAA gene. In previous studies, Yan et al. (2001) had found that HRY, binding to the same element of the GAA gene in hepatoma cells, acts as a GAA transcription silencer. Yan et al. (2002) noted that the dual function of HRY is likely to contribute to the subtle tissue-specific control of housekeeping genes such as GAA.
Hirata et al. (2002) demonstrated that serum treatment of cultured cells induces cyclic expression of both mRNA and protein of the NOTCH effector HES1 with 2-hour periodicity. Cycling is cell-autonomous and depends on negative autoregulation of HES1 transcription and ubiquitin-proteasome-mediated degradation of HES1 protein. Because HES1 oscillation can be seen in many cell types, Hirata et al. (2002) suggested that this clock may regulate timing in many biologic systems.
Shen et al. (2004) demonstrated that endothelial cells but not vascular smooth muscle cells release soluble factors that stimulate the self-renewal of neural stem cells, inhibit their differentiation, and enhance their neuron production. Both embryonic and adult neural stem cells respond, allowing extensive production of both projection neuron and interneuron types in vitro. Endothelial coculture stimulated neuroepithelial cell contact, activating Notch (190198) and HES1 to promote self-renewal. These findings identified endothelial cells as a critical component of the neural stem cell niche.
Sang et al. (2008) reported that reversibility of quiescence is not a passive property of nondividing cells, because enforced cell cycle arrest for a period as brief as 4 days initiates spontaneous, premature, and irreversible senescence. Increased expression of the gene encoding HES1 was required for quiescence to be reversible, because HES1 prevented both premature senescence and inappropriate differentiation in quiescent fibroblasts. In some human tumors, the HES1 pathway was activated, which allowed these cells to evade differentiation and irreversible cell cycle arrest. Sang et al. (2008) concluded that HES1 safeguards against irreversible cell cycle exit both during normal cellular quiescence and pathologically in the setting of tumorigenesis.
Fanconi anemia (FA; 227650) is a congenital form of aplastic anemia that can be caused by mutation in any of the genes encoding components of the FA core complex, which functions in chromosome stability and repair of DNA crosslinks. Hematopoietic stem cells (HSCs) of FA patients have reduced self-renewal and reconstitution abilities and increased cycling activity, resulting in progressive depletion of HSCs and bone marrow failure. Tremblay et al. (2008) found that HES1 interacted directly with the FA core complex components FANCA (607139), FANCF (603467), FANCG (XRCC9; 602956), and FANCL (PHF9; 608111). Mutation analysis showed that interactions with individual FA core components required different domains within HES1. HES1 did not interact with FA core components if any of them contained an FA-related mutation, suggesting that a functional FA pathway is required for HES1 interaction. Depletion of HES1 from HeLa cells resulted in failure of normal interactions between individual FA core components, as well as altered protein levels and mislocalization of some FA core components. Cell hypersensitivity to mitomycin C (MMC), a DNA crosslinking agent, is a hallmark of FA cells. Endogenous HES1 localized to MMC-induced foci in MMC-treated HeLa cells, but it did not localize to MMC-induced foci in FANCA mutant cells unless normal FANCA levels were restored. Depletion of HES1 alone also increased cell sensitivity to MMC. Furthermore, HES1 depletion reduced monoubiquitination of FANCD2 (227646) in response to MMC and, consequently, it reduced localization of FANCD2 to MMC-induced foci. Tremblay et al. (2008) concluded that interaction with HES1 is required for normal FA core complex function in the DNA damage response. They proposed that the HSC defect in FA may result from the inability of HES1 to interact with the defective FA core complex.
The basic helix-loop-helix transcription factors ASCL1 (100790), HES1, and OLIG2 (606386) regulate fate choice of neurons, astrocytes, and oligodendrocytes, respectively. These same factors are coexpressed by neural progenitor cells. Imayoshi et al. (2013) found by time-lapse imaging that these factors are expressed in an oscillatory manner by mouse neural progenitor cells. In each differentiation lineage, 1 of the factors becomes dominant. Imayoshi et al. (2013) used optogenetics to control expression of Ascl1 and found that, although sustained Ascl1 expression promotes neuronal fate determination, oscillatory Ascl1 expression maintains proliferating neural progenitor cells. Imayoshi et al. (2013) concluded that the multipotent state correlates with oscillatory expression of several fate-determination factors, whereas the differentiated state correlates with sustained expression of a single factor.
Feder et al. (1994) determined that the HES1 gene contains 4 coding exons. Analysis of the DNA sequence 5-prime to the HES1 coding region demonstrated a putative untranslated exon.
By fluorescence in situ hybridization, Feder et al. (1994) assigned the HES1 gene to chromosome 3q28-q29.
Votruba et al. (1998) refined the position of the HES1 gene, placing it telomeric to marker D3S3562 and centromeric to D3S1305. This mapping placed the HES1 gene outside the critical disease interval for autosomal dominant optic atrophy (OPA1; 165500).
Votruba et al. (1998) identified no mutations in the HRY gene in 36 patients from 18 pedigrees with OPA1. Using a polymorphism in the untranslated region of exon 2 of HRY, Votruba et al. (1998) found recombination between HRY and OPA1 in 1 pedigree.
Isolated Juvenile or Chronic Myelomonocytic Leukemia
Klinakis et al. (2011) identified novel somatic inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukemia (CMML; see 607785). Inactivation of Notch signaling in mouse hematopoietic stem cells resulted in aberrant accumulation of granulocyte/monocyte progenitors, extramedullary hematopoiesis, and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signaling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1. Klinakis et al. (2011) concluded that their studies identified a novel role for Notch signaling during early hematopoietic stem cell differentiation and suggested that the Notch pathway can play both tumor-promoting and -suppressive roles within the same tissue.
The biliary system, pancreas, and liver all develop from the nearby foregut at almost the same time in mammals. Sumazaki et al. (2004) contributed to the understanding of the molecular mechanisms that determine the identity of each organ in this complex area. HES1 protein represses positive basic helix-loop-helix genes such as NEUROG3 (604882). Expression of HES1 is controlled by the evolutionarily conserved Notch pathway. Sumazaki et al. (2004) showed that HES1 is expressed in the extrahepatic biliary epithelium throughout development and that Hes1-deficient mice have gallbladder agenesis and severe hypoplasia of extrahepatic bile ducts. Biliary epithelium in Hes1 -/- mice ectopically expressed the proendocrine gene Neurog3, differentiated into endocrine and exocrine cells, and formed acini and islet-like structures in the mutant bile ducts. Thus, biliary epithelium has the potential for pancreatic differentiation and Hes1 determines biliary organogenesis by preventing the pancreatic differentiation program, probably by directly repressing transcription of Neurog3.
Fukuda et al. (2006) found that Hes1 inactivation in mice induced misexpression of pancreas transcription factor-1-alpha (Ptf1a; 607194) in discrete regions of the primitive stomach and duodenum and throughout the common bile duct. Lineage tracing revealed that all ectopic Ptf1a-expressing cells were transcommitted to multipotent pancreatic progenitor status and subsequently differentiated into mature pancreatic exocrine, endocrine, and duct cells.
Using mice with conditional inactivation of Hes1 or intrathymic transfers, Wendorff et al. (2010) showed that adult bone marrow had severely impaired development of T cells, but not other Notch-dependent hematopoietic lineages. Hes1 was required for T-cell lineage commitment, but it was dispensable for Notch-dependent thymocyte maturation through and beyond the beta checkpoint. Wendorff et al. (2010) also presented data suggesting that Hes1 is essential for Notch-induced T-cell acute lymphoblastic leukemia. Wendorff et al. (2010) concluded that HES1 is a critical, context-dependent mediator of canonical NOTCH signaling in the hematopoietic system.
Feder, J. N., Li, L., Jan, L. Y., Jan, Y. N. Genomic cloning and chromosomal localization of HRY, the human homolog of the Drosophila segmentation gene, hairy. Genomics 20: 56-61, 1994. [PubMed: 8020957] [Full Text: https://doi.org/10.1006/geno.1994.1126]
Fukuda, A., Kawaguchi, Y., Furuyama, K., Kodama, S., Horiguchi, M., Kuhara, T., Koizumi, M., Boyer, D. F., Fujimoto, K., Doi, R., Kageyama, R., Wright, C. V. E., Chiba, T. Ectopic pancreas formation in Hes1-knockout mice reveals plasticity of endodermal progenitors of the gut, bile duct, and pancreas. J. Clin. Invest. 116: 1484-1493, 2006. [PubMed: 16710472] [Full Text: https://doi.org/10.1172/JCI27704]
Hirata, H., Yoshiura, S., Ohtsuka, T., Bessho, Y., Harada, T., Yoshikawa, K., Kageyama, R. Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop. Science 298: 840-843, 2002. [PubMed: 12399594] [Full Text: https://doi.org/10.1126/science.1074560]
Imayoshi, I., Isomura, A., Harima, Y., Kawaguchi, K., Kori, H., Miyachi, H., Fujiwara, T., Ishidate, F., Kageyama, R. Oscillatory control of factors determining multipotency and fate in mouse neural progenitors. Science 342: 1203-1208, 2013. [PubMed: 24179156] [Full Text: https://doi.org/10.1126/science.1242366]
Klinakis, A., Lobry, C., Abdel-Wahab, O., Oh, P., Haeno, H., Buonamici, S., van De Walle, I., Cathelin, S., Trimarchi, T., Araldi, E., Liu, C., Ibrahim, S., Beran, M., Zavadil, J., Efstratiadis, A., Taghon, T., Michor, F., Levine, R. L., Aifantis, I. A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature 473: 230-233, 2011. [PubMed: 21562564] [Full Text: https://doi.org/10.1038/nature09999]
Sang, L., Coller, H. A., Roberts, J. M. Control of the reversibility of cellular quiescence by the transcriptional repressor HES1. Science 321: 1095-1100, 2008. [PubMed: 18719287] [Full Text: https://doi.org/10.1126/science.1155998]
Shen, Q., Goderie, S. K., Jin, L., Karanth, N., Sun, Y., Abramova, N., Vincent, P., Pumiglia, K., Temple, S. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304: 1338-1340, 2004. [PubMed: 15060285] [Full Text: https://doi.org/10.1126/science.1095505]
Sumazaki, R., Shiojiri, N., Isoyama, S., Masu, M., Keino-Masu, K., Osawa, M., Nakauchi, H., Kageyama, R., Matsui, A. Conversion of biliary system to pancreatic tissue in Hes1-deficient mice. Nature Genet. 36: 83-87, 2004. [PubMed: 14702043] [Full Text: https://doi.org/10.1038/ng1273]
Tremblay, C. S., Huang, F. F., Habi, O., Huard, C. C., Godin, C., Levesque, G., Carreau, M. HES1 is a novel interactor of the Fanconi anemia core complex. Blood 112: 2062-2070, 2008. Note: Erratum: Blood 114: 3974 only, 2009. [PubMed: 18550849] [Full Text: https://doi.org/10.1182/blood-2008-04-152710]
Votruba, M., Payne, A., Moore, A. T., Bhattacharya, S. S. Dominant optic atrophy: exclusion and fine genetic mapping of the candidate gene, HRY. Mammalian Genome 9: 784-787, 1998. [PubMed: 9745030] [Full Text: https://doi.org/10.1007/s003359900867]
Wendorff, A. A., Koch, U., Wunderlich, F. T., Wirth, S., Dubey, C., Bruning, J. C., MacDonald, H. R., Radtke, F. Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation. Immunity 33: 671-684, 2010. [PubMed: 21093323] [Full Text: https://doi.org/10.1016/j.immuni.2010.11.014]
Yan, B., Heus, J., Lu, N., Nichols, R. C., Raben, N., Plotz, P. H. Transcriptional regulation of the human acid alpha-glucosidase gene: identification of a repressor element and its transcription factors Hes-1 and YY1. J. Biol. Chem. 276: 1789-1793, 2001. [PubMed: 11038350] [Full Text: https://doi.org/10.1074/jbc.M005959200]
Yan, B., Raben, N., Plotz, P. H. Hes-1, a known transcriptional repressor, acts as a transcriptional activator for the human acid alpha-glucosidase gene in human fibroblast cells. Biochem. Biophys. Res. Commun. 291: 582-587, 2002. [PubMed: 11855828] [Full Text: https://doi.org/10.1006/bbrc.2002.6483]