Transcription factor HES1 (hairy and enhancer of split-1) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that is encoded by the ''Hes1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
, and is the mammalian homolog of the hairy gene in ''
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
.''
HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription.
This protein belongs to the basic
helix-loop-helix (bHLH) family of
transcription factors
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...
. 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 canonical
enhancer box (E-box).
As a member of the bHLH family, it is a transcriptional repressor that influences cell proliferation and differentiation in
embryogenesis
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
.
HES1 regulates its own expression via a
negative feedback loop
Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by other ...
, and oscillates with approximately 2-hour periodicity.
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
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
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).
The Orange domain serves to regulate the choice of bHLH
heterodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
partners. The
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
WRPW domain inhibits transcription.
Interactions
Similarly to other HES proteins, Hes1 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
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''. 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
Hairy/enhancer-of-split related with YRPW motif protein 1 is a protein that in humans is encoded by the ''HEY1'' gene.
Function
This gene encodes a nuclear protein belonging to the hairy and enhancer of split-related (HESR) family of basic hel ...
and
Hey2
Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2) also known as cardiovascular helix-loop-helix factor 1 (CHF1) is a protein that in humans is encoded by the ''HEY2'' gene.
This protein is a type of transcription factor that belong ...
, 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
Achaete-scute homolog 1 is a protein that in humans is encoded by the ''ASCL1'' gene. Because it was discovered subsequent to studies on its homolog in Drosophila, the Achaete-scute complex, it was originally named MASH-1 for mammalian achaete scu ...
, 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.
Hes1 also interacts with
TLE2
Transducin-like enhancer protein 2 is a protein that in humans is encoded by the ''TLE2'' gene.
Interactions
TLE2 has been shown to interact with TLE1 and HES1
Transcription factor HES1 (hairy and enhancer of split-1) is a protein that is enc ...
and
Sirtuin 1
Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.
SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (''S. cerevisiae''), referring to the fact t ...
.
HES1 and stem cells
HES1 influences the maintenance of certain
stem cells
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
and
progenitor cells
In genealogy, the progenitor (rarer: primogenitor; german: Stammvater or ''Ahnherr'') is the – sometimes legendary – founder of a family, line of descent, clan or tribe, noble house, or ethnic group..
Ebenda''Ahnherr:''"Stammvater eines G ...
. 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 the
nervous, and
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 Neuroepithelial cells, or neuroectodermal cells, form the wall of the closed neural tube in early embryonic development. The neuroepithelial cells span the thickness of the tube's wall, connecting with the pial surface and with the ventricular or l ...
and
radial glial cell
Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and ol ...
s, both neural stem cells. ''Hes1'' expression, along with that of ''Hes5'', covers the majority of the developing embryo at embryonic day 10.5. After this point, expression of ''Hes1'' is limited to the
subventricular zone
The subventricular zone (SVZ) is a region situated on the outside wall of each lateral ventricle of the vertebrate brain. It is present in both the embryonic and adult brain. In embryonic life, the SVZ refers to a secondary proliferative 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.
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
Pax6
Paired box protein Pax-6, also known as aniridia type II protein (AN2) or oculorhombin, is a protein that in humans is encoded by the ''PAX6'' gene.
Function
PAX6 is a member of the Pax gene family which is responsible for carrying the geneti ...
, but leads cells that are Pax6-negative to an
astrocyte
Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...
differentiation fate.
Epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
modifications such as
DNA methylation
DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts t ...
also influence HES1's ability to direct differentiation. Demethylation of HES1 target sites in the promoter region of astrocyte-specific genes hastens astrocyte differentiation.
The oscillatory nature of ''Hes1'' 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 using
quantitative PCR
A real-time polymerase chain reaction (real-time PCR, or qPCR) is a laboratory technique of molecular biology based on the polymerase chain reaction (PCR). It monitors the amplification of a targeted DNA molecule during the PCR (i.e., in real ...
which showed that HES1-high cells showed high levels of ''
Brachyury
T-box transcription factor T, also known as Brachyury protein, is encoded for in humans by the ''TBXT'' gene. Brachyury functions as a transcription factor within the T-box family of genes. Brachyury homologs have been found in all bilaterian an ...
'' 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.
Cycling HES1 levels also contribute to the maintenance of neural progenitor cells by regulating Neurogenin2 (Ngn2) and Dll1 oscillations. ''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.
Interactions with the Notch pathway
HES1 also plays an important role in the
Notch signaling pathway
The Notch signaling pathway is a highly Conserved sequence, conserved cell signaling system present in most animals. Mammals possess four different Notch proteins, notch receptors, referred to as NOTCH1, NOTCH2, Notch 3, NOTCH3, and NOTCH4. The ...
. In the absence of Notch signaling,
RBPJ
Recombination signal binding protein for immunoglobulin kappa J region is a protein that in humans is encoded by the ''RBPJ'' gene.
RBPJ also known as CBF1, is the human homolog for the Drosophila gene Suppressor of Hairless. Its promoter region ...
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.
, ''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. Notch signaling also occurs in the
intestinal crypt cells. Hyperactivated Notch causes a reduction in the number of secretory cell types (i.e.
goblet cells
Goblet cells are simple columnar epithelial cells that secrete gel-forming mucins, like mucin 5AC. The goblet cells mainly use the merocrine method of secretion, secreting vesicles into a duct, but may use apocrine methods, budding off their secre ...
,
enteroendocrine cells
Enteroendocrine cells are specialized cells of the gastrointestinal tract and pancreas with endocrine function. They produce gastrointestinal hormones or peptides in response to various stimuli and release them into the bloodstream for systemic ef ...
, and
Paneth cells
Paneth cells are cells in the small intestine epithelium, alongside goblet cells, enterocytes, and enteroendocrine cells. Some can also be found in the cecum and vermiform appendix, appendix. They are below the intestinal stem cells in the intest ...
). Deletion of the Notch pathway by removing the Notch expression controller, ''Rbpsuh'', causes the production of nearly only goblet cells.
Digestive system
HES1 has been shown to influence the differentiation decision of cells in the gastrointestinal tract. In
pancreatic progenitor cells, HES1 expression inhibits the expression of
''Ptf1a'', which controls exocrine cell differentiation, and
Ngn3
Neurogenins are a family of bHLH transcription factors involved in specifying neuronal differentiation. It is one of many gene families related to the ''atonal'' gene in Drosophila. Other positive regulators of neuronal differentiation also exp ...
, which drives differentiation of endocrine cell types that will form the
islets of Langerhans
The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of ...
.
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.
, Liver progenitor cells differentiate into two different cell types:
hepatocytes
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, b ...
and
biliary epithelial cells. When ''Hes1'' expression is low, hepatocytes form normally, but bile ducts are completely absent.
This phenotype resembles
Alagille syndrome
Alagille syndrome is a genetic disorder that affects primarily the liver and the heart. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and t ...
, a hallmark of which is mutations in ''Jagged1''. Therefore, Hes-Notch interactions also play a role in digestive organ development.
References
Further reading
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
External links
*
{{Transcription factors, g1
Transcription factors