Transcription factor HES1 (hairy and enhancer of split-1) is aprotein that is encoded by theHes1gene, and is the mammalian homolog of the hairy gene inDrosophila.[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 basichelix-loop-helix (bHLH) family oftranscription factors. It is a transcriptional repressor of genes that require a bHLH protein for their transcription. The protein has a particular type of basic domain that contains a helix interrupting protein that binds to the N-box promoter region rather than the canonicalenhancer box (E-box).[6] As a member of the bHLH family, it is a transcriptional repressor that influences cell proliferation and differentiation inembryogenesis.[7] HES1 regulates its own expression via anegative feedback loop, and oscillates with approximately 2-hour periodicity.[8]
There are three conserveddomains in Hes genes that impart transcriptional functions: the bHLH domain, theOrange domain, and the WRPW motif. Hes genes differ from other bHLH factors in that they have aproline 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 bHLHheterodimer partners.[9] TheC-terminal WRPW domain inhibits transcription.[10]
Similarly to other HES proteins, Hes1 has been shown tointeract with the co-repressors encoded by the Transducin-like E(spl) (TLE) genes and the Groucho-related gene (Grg), both homologs of theDrosophila groucho.[11] Because Groucho inDrosophila 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 asHey1 andHey2, a process which also blocks transcription. Hes factors also heterodimerize with bHLH activators such as E47, also known as Tcfe2a, and Mash1, also known asAscl1, both of which are the mammalian homologs to proneural genes inDrosophila. The E47-Hes and Mash1-Hes heterodimer complexes cannot bind DNA, and therefore repress transcription.[7]Hes1 also interacts withTLE2[12] andSirtuin 1.[13]
HES1 influences the maintenance of certainstem cells andprogenitor cells. Specifically, HES1 influences the timing of differentiation by repressing bHLH activators, and determines binary cell fate. HES1 has been shown to play a large role in both thenervous, anddigestive systems. HES1 has been shown to influence these two systems partially through the Notch signaling pathway.
HES1 is expressed in bothneuroepithelial cells andradial glial cells, both neural stem cells.Hes1 expression, along with that ofHes5, covers the majority of the developing embryo at embryonic day 10.5.[14] After this point, expression ofHes1 is limited to thesubventricular zone. In HES1knockout (KO) mice, Mash1 is compensatorily upregulated, and neurogenesis is accelerated. Indeed, if the expression ofHes1,Hes3, andHes5 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 expressingPax6, but leads cells that are Pax6-negative to anastrocyte differentiation fate.[16]Epigenetic modifications such asDNA methylation also influence HES1's ability to direct differentiation. Demethylation of HES1 target sites in the promoter region of astrocyte-specific genes hastens astrocyte differentiation.[15] The oscillatory nature ofHes1 expression has a role in determining differentiation fate as well. HES1-high embryonic stem cells that received a differentiation signal often adopted a mesodermal fate, while HES1-low cells that received a differentiation signal differentiated into neuronal cells. These results were confirmed usingquantitative PCR which showed that HES1-high cells showed high levels ofBrachyury andFgf5 expression (both of which are expressed highly in mesodermal cell types) with comparatively low levels genes expressed in neural cells such asNestin. 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]
HES1 also plays an important role in theNotch signaling pathway.[19] In the absence of Notch signaling,RBPJ inhibits the expression of HES1. After Notch signals have been processed within the cell, however, the plasma membrane releases the intracellular domain of Notch, which moves to the nucleus where it associates with RBPJ. The binding causes a conformational change which leads co-repressors to disassociate and allows co-activators to bind. The new activating complex then prompts HES1 expression. Notch signaling activates HES1 expression. HES1 has been shown to target at least Notch ligands:Dll1,Jagged1 (Jag1), and Neurogenin-2.[15],[17]Dll1, as with other Notch ligands, has been shown to induce neural differentiation, and HES1 binding of Dll1 blocks neural differentiation and leads to the maintenance of the neural stem cells and neural progenitor cells.[20] Notch signaling also occurs in theintestinal crypt cells. Hyperactivated Notch causes a reduction in the number of secretory cell types (i.e.goblet cells,enteroendocrine cells, andPaneth cells). Deletion of the Notch pathway by removing the Notch expression controller,Rbpsuh, causes the production of nearly only goblet cells.[21]
HES1 has been shown to influence the differentiation decision of cells in the gastrointestinal tract. Inpancreatic progenitor cells, HES1 expression inhibits the expression ofPtf1a, which controls exocrine cell differentiation, andNgn3, which drives differentiation of endocrine cell types that will form theislets of Langerhans.[7] The absence ofHes1 in the developing intestine of mice promotes the increase ofMath1 (a protein required for the production of intestinal secretory cell types), which leads to an increase of goblet, enteroendocrine, and Paneth cells. WhenHes1 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 andbiliary epithelial cells. WhenHes1 expression is low, hepatocytes form normally, but bile ducts are completely absent.[22] This phenotype resemblesAlagille syndrome, a hallmark of which is mutations inJagged1. Therefore, Hes-Notch interactions also play a role in digestive organ development.
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