Hes Family BHLH Transcription Factor 4 (HES4) is aprotein encoded by agene of the same name located onchromosome 1 in humans.[3] It does not currently have a known mouseortholog.
HES4 plays a major role in key developmental processes, particularly in theimmune system andbone formation. As a member of thebasic helix-loop-helix (bHLH) family oftranscription factors, HES4 plays a crucial role inT-cell development by responding toNotch1 signaling, which is vital for guidinghematopoietic progenitor cells toward becomingT-cells.[4]
Additionally, HES4 has emerged as a significant factor in the context ofosteosarcoma (OS), a type ofbone cancer, where its expression correlates with aggressivetumor behavior and poor patient prognosis.[5]
HES4 is apolypeptide chain consisting of 221amino acids with amolecular weight of 23,523 Da.[6]
The secondary structure of the completed HES4 protein features a structural motif known as thebasic helix-loop-helix (bHLH).[7] This motif is characterized by twoalpha helices connected by a loop, which allows for a compact and flexible structure.[8]
The bHLH domain plays a critical role inDNA binding andprotein-protein interactions, making it significant in various biological processes, particularly in the regulation ofgene expression.[8] In HES4, the basic region of the motif typically contains positively chargedamino acids that facilitate binding to specific DNA sequences, often in the context oftranscriptional regulation.
HES4 plays an important role in the development ofT-cells, which are a type ofwhite blood cell that are a crucial part of the mammalianimmune system. The process ofT-cell development starts when a signaling pathway called Notch1 is activated in certain blood precursor cells, known ashematopoietic progenitor cells.
Notch1 activation is crucial for initiatingT-cell development while suppressingdifferentiation into other lineages. While the functions of these genes are well understood inmice, the absence of a mouseortholog for HES4 has made its role in humans less clear.
WhenNotch1 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 orred 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 calledHES1. 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 becomeT-cells. In contrast, HES4 also supports the early stages ofT-cell development but does not prevent the formation ofB-cells, another important type of immune cell.[4]
Together, HES4 andHES1 ensure that as blood precursor cells receive theNotch1 signal, so that they successfully start their journey to becoming T-cells.
BecauseT-cells play an important role in constantly scrutinizing and destroyingtumor cells,[9] and HES4 is important for the development ofT-cells in humans, it has been hypothesised to be anoncogene and has been investigated usinghuman cell lines andmice.
The clinical significance of HES4 inosteosarcoma (OS) is highlighted by its potential as aprognostic biomarker.
Studies using human OS cell lines bothin vitro and injecting them into live micein vivo have confirmed that overexpressing HES4 leads to larger and more aggressivetumors, with agreater tendency to spread to other parts of the body.[5]
Interestingly, while overexpressing HES4 promotes aggressive tumor behavior by inhibiting the normalbone cell differentiation process, anotherNotch1 target gene,HES1, has opposing effects, where overexpression has a preventative effect on tumor growth.[5]
