HES1

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HES1
Available structures
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl
UniProt
RefSeq (mRNA)

NM_005524

NM_008235

RefSeq (protein)

NP_005515

NP_032261

Location (UCSC)Chr 3: 194.14 – 194.14 MbChr 16: 29.88 – 29.89 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Transcription factor HES1 (hairy and enhancer of split-1) is a protein that is encoded by the Hes1 gene, and is the mammalian homolog of the hairy gene in Drosophila.[5][6] HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription.[7]

This protein belongs to the basic

negative feedback loop, and oscillates with approximately 2-hour periodicity.[8]

Structure

There are three conserved domains in Hes genes that impart transcriptional functions: the bHLH domain, the Orange domain, and the WRPW motif. Hes genes differ from other bHLH factors in that they have a proline residue in the middle of the basic DNA binding region. This proline has been proposed to give Hes proteins unique DNA binding capacity. While most bHLH factors bind to the E-box consensus sequence (CANNTG) that is present in the promoter region of target genes, Hes factors bind more preferentially to the Class C site or N box (CACNAG).[7] The Orange domain serves to regulate the choice of bHLH heterodimer partners.[9] The C-terminal WRPW domain inhibits transcription.[10]

Interactions

Similarly to other HES proteins, Hes1 has been shown to

interact with the co-repressors encoded by the Transducin-like E(spl) (TLE) genes and the Groucho-related gene (Grg), both homologs of the Drosophila groucho.[11] Because Groucho in Drosophila inhibits transcription by recruiting histone deacetylase, it is likely that a Hes-Groucho complex actively blocks transcription by disabling chromatin. Hes proteins also heterodimerize with bHLH repressors such as Hey1 and Hey2, a process which also blocks transcription. Hes factors also heterodimerize with bHLH activators such as E47, also known as Tcfe2a, and Mash1, also known as Ascl1, both of which are the mammalian homologs to proneural genes in Drosophila. The E47-Hes and Mash1-Hes heterodimer complexes cannot bind DNA, and therefore repress transcription.[7]
Hes1 also interacts with TLE2[12] and Sirtuin 1.[13]

HES1 and stem cells

HES1 influences the maintenance of certain

digestive
systems. HES1 has been shown to influence these two systems partially through the Notch signaling pathway.

Neural development

HES1 is expressed in both

neuroepithelial cells and radial glial cells, both neural stem cells. Hes1 expression, along with that of Hes5, covers the majority of the developing embryo at embryonic day 10.5.[14] After this point, expression of Hes1 is limited to the subventricular zone. In HES1 knockout (KO) mice, Mash1 is compensatorily upregulated, and neurogenesis is accelerated. Indeed, if the expression of Hes1, Hes3, and Hes5 genes is inhibited, the expression of proneural genes increases, and while neurogenesis is accelerated, neural stem cells become prematurely depleted. Contrariwise, if these HES genes are overexpressed, neurogenesis is inhibited.[15]
Thus HES1 genes are only involved in maintaining, not creating, neural stem cells.

Additionally, HES1 can guide neural stem cells down one of two paths of differentiation. HES1 can maintain neural stem cells expressing

Brachyury and Fgf5 expression (both of which are expressed highly in mesodermal cell types) with comparatively low levels genes expressed in neural cells such as Nestin. By contrast, HES1-low cells showed high levels of expression of genes involved in neural induction and low levels of expression of genes involved in mesodermal differentiation.[17] Cycling HES1 levels also contribute to the maintenance of neural progenitor cells by regulating Neurogenin2 (Ngn2) and Dll1 oscillations.[18] Hes1 levels fluctuate at different frequencies in different parts of the central nervous system: HES1 is continuously expressed at high levels in the boundaries, but vacillates in the compartments. This suggests that alternating HES1 levels may prompt differences in characteristics between anatomical elements of the central nervous system.[7]

Interactions with the Notch pathway

HES1 also plays an important role in the

Paneth cells). Deletion of the Notch pathway by removing the Notch expression controller, Rbpsuh, causes the production of nearly only goblet cells.[21]

Digestive system

HES1 has been shown to influence the differentiation decision of cells in the gastrointestinal tract. In

islets of Langerhans.[7] The absence of Hes1 in the developing intestine of mice promotes the increase of Math1 (a protein required for the production of intestinal secretory cell types), which leads to an increase of goblet, enteroendocrine, and Paneth cells. When Hes1 is deleted in mouse and zebrafish, surplus goblet cells and enteroendocrine cells are made while few enterocytes are made.[7], [21] Liver progenitor cells differentiate into two different cell types: hepatocytes and biliary epithelial cells. When Hes1 expression is low, hepatocytes form normally, but bile ducts are completely absent.[22] This phenotype resembles Alagille syndrome
, a hallmark of which is mutations in Jagged1. Therefore, Hes-Notch interactions also play a role in digestive organ development.

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000114315 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022528 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. PMID 8020957
    .
  6. ^ a b "Entrez Gene: HES1 hairy and enhancer of split 1, (Drosophila)".
  7. ^
    S2CID 1693293
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Further reading

External links

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

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