Hes Family BHLH Transcription Factor 4 (HES4) is a protein encoded by a gene of the same name located on chromosome 1 in humans. [3] It does not currently have a known mouse ortholog.
HES4 plays a major role in key developmental processes, particularly in the immune system and bone formation. As a member of the basic helix-loop-helix (bHLH) family of transcription factors, HES4 plays a crucial role in T-cell development by responding to Notch1 signaling, which is vital for guiding hematopoietic progenitor cells toward becoming T-cells. [4]
Additionally, HES4 has emerged as a significant factor in the context of osteosarcoma (OS), a type of bone cancer, where its expression correlates with aggressive tumor behavior and poor patient prognosis. [5]
HES4 is a polypeptide chain consisting of 221 amino acids with a molecular weight of 23,523 Da. [6]
The secondary structure of the completed HES4 protein features a structural motif known as the basic helix-loop-helix (bHLH). [7] This motif is characterized by two alpha helices connected by a loop, which allows for a compact and flexible structure. [8]
The bHLH domain plays a critical role in DNA binding and protein-protein interactions, making it significant in various biological processes, particularly in the regulation of gene expression. [8] In HES4, the basic region of the motif typically contains positively charged amino acids that facilitate binding to specific DNA sequences, often in the context of transcriptional regulation.
HES4 plays an important role in the development of T-cells, which are a type of white blood cell that are a crucial part of the mammalian immune system. The process of T-cell development starts when a signaling pathway called Notch1 is activated in certain blood precursor cells, known as hematopoietic progenitor cells.
Notch1 activation is crucial for initiating T-cell development while suppressing differentiation into other lineages. While the functions of these genes are well understood in mice, the absence of a mouse ortholog for HES4 has made its role in humans less clear.
When Notch1 is activated, it acts like a switch that encourages these cells to become T-cells instead of other types of blood cells, such as those involved in the immune response or red blood cell formation. HES4 is one of the genes that responds to this activation, helping to guide the cells along the T-cell development path.
Research has shown that HES4 works alongside another gene called HES1. While both genes help suppress the development of other cell types, they do so in different ways. HES1 primarily keeps the cells in a resting state, allowing them to maintain their potential to become T-cells. In contrast, HES4 also supports the early stages of T-cell development but does not prevent the formation of B-cells, another important type of immune cell. [4]
Together, HES4 and HES1 ensure that as blood precursor cells receive the Notch1 signal, so that they successfully start their journey to becoming T-cells.
Because T-cells play an important role in constantly scrutinizing and destroying tumor cells, [9] and HES4 is important for the development of T-cells in humans, it has been hypothesised to be an oncogene and has been investigated using human cell lines and mice.
The clinical significance of HES4 in osteosarcoma (OS) is highlighted by its potential as a prognostic biomarker.
Studies using human OS cell lines both in vitro and injecting them into live mice in vivo have confirmed that overexpressing HES4 leads to larger and more aggressive tumors, with a greater tendency to spread to other parts of the body. [5]
Interestingly, while overexpressing HES4 promotes aggressive tumor behavior by inhibiting the normal bone cell differentiation process, another Notch1 target gene, HES1, has opposing effects, where overexpression has a preventative effect on tumor growth. [5]
A basic helix–loop–helix (bHLH) is a protein structural motif that characterizes one of the largest families of dimerizing transcription factors. The word "basic" does not refer to complexity but to the chemistry of the motif because transcription factors in general contain basic amino acid residues in order to facilitate DNA binding.
Inhibitor of DNA-binding/differentiation proteins, also known as ID proteins comprise a family of proteins that heterodimerize with basic helix-loop-helix (bHLH) transcription factors to inhibit DNA binding of bHLH proteins. ID proteins also contain the HLH-dimerization domain but lack the basic DNA-binding domain and thus regulate bHLH transcription factors when they heterodimerize with bHLH proteins. The first helix-loop-helix proteins identified were named E-proteins because they bind to Ephrussi-box (E-box) sequences. In normal development, E proteins form dimers with other bHLH transcription factors, allowing transcription to occur. However, in cancerous phenotypes, ID proteins can regulate transcription by binding E proteins, so no dimers can be formed and transcription is inactive. E proteins are members of the class I bHLH family and form dimers with bHLH proteins from class II to regulate transcription. Four ID proteins exist in humans: ID1, ID2, ID3, and ID4. The ID homologue gene in Drosophila is called extramacrochaetae (EMC) and encodes a transcription factor of the helix-loop-helix family that lacks a DNA binding domain. EMC regulates cell proliferation, formation of organs like the midgut, and wing development. ID proteins could be potential targets for systemic cancer therapies without inhibiting the functioning of most normal cells because they are highly expressed in embryonic stem cells, but not in differentiated adult cells. Evidence suggests that ID proteins are overexpressed in many types of cancer. For example, ID1 is overexpressed in pancreatic, breast, and prostate cancers. ID2 is upregulated in neuroblastoma, Ewing’s sarcoma, and squamous cell carcinoma of the head and neck.
Myogenin, is a transcriptional activator encoded by the MYOG gene. Myogenin is a muscle-specific basic-helix-loop-helix (bHLH) transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair. Myogenin is a member of the MyoD family of transcription factors, which also includes MyoD, Myf5, and MRF4.
Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.
DNA-binding protein inhibitor ID-1 is a protein that in humans is encoded by the ID1 gene.
Transcription factor HES1 is a protein that is encoded by the Hes1 gene, and is the mammalian homolog of the hairy gene in Drosophila. HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription.
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 scute homolog-1.
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.
Rhombotin-1 is a protein that in humans is encoded by the LMO1 gene.
ID4 is a protein coding gene. In humans, it encodes the protein known as DNA-binding protein inhibitor ID-4. This protein is known to be involved in the regulation of many cellular processes during both prenatal development and tumorigenesis. This is inclusive of embryonic cellular growth, senescence, cellular differentiation, apoptosis, and as an oncogene in angiogenesis.
Heart- and neural crest derivatives-expressed protein 1 is a protein that in humans is encoded by the HAND1 gene.
Protein atonal homolog 1 is a protein that in humans is encoded by the ATOH1 gene.
Transcription factor 21 (TCF21), also known as pod-1, capsuling, or epicardin, is a protein that in humans is encoded by the TCF21 gene on chromosome 6. It is ubiquitously expressed in many tissues and cell types and highly significantly expressed in lung and placenta. TCF21 is crucial for the development of a number of cell types during embryogenesis of the heart, lung, kidney, and spleen. TCF21 is also deregulated in several types of cancers, and thus known to function as a tumor suppressor. The TCF21 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
Achaete-scute complex homolog 2 (Drosophila), also known as ASCL2, is an imprinted human gene.
Transcription factor AP-4 , also known as TFAP4, is a protein which in humans is encoded by the TFAP4 gene.
Hairy/enhancer-of-split related with YRPW motif-like protein is a protein that in humans is encoded by the HEYL gene.
"Basic helix-loop-helix family, member e41", or BHLHE41, is a gene that encodes a basic helix-loop-helix transcription factor repressor protein in various tissues of both humans and mice. It is also known as DEC2, hDEC2, and SHARP1, and was previously known as "basic helix-loop-helix domain containing, class B, 3", or BHLHB3. BHLHE41 is known for its role in the circadian molecular mechanisms that influence sleep quantity as well as its role in immune function and the maturation of T helper type 2 cell lineages associated with humoral immunity.
T-cell acute lymphocytic leukemia 2, also known as TAL2, is a protein which in humans is encoded by the TAL2 gene.
Basic helix-loop-helix ARNT-like protein 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), or brain and muscle ARNT-like 1 is a protein that in humans is encoded by the BMAL1 gene on chromosome 11, region p15.3. It's also known as MOP3, and, less commonly, bHLHe5, BMAL, BMAL1C, JAP3, PASD3, and TIC.
dClock (clk) is a gene located on the 3L chromosome of Drosophila melanogaster. Mapping and cloning of the gene indicates that it is the Drosophila homolog of the mouse gene CLOCK (mClock). The Jrk mutation disrupts the transcription cycling of per and tim and manifests dominant effects.