Hes Family BHLH Transcription Factor 4 (HES4) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

encoded by a

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

of the same name located on

chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which a ...

in humans. It does not currently have a known mouse

ortholog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...

. HES4 plays a major role in key developmental processes, particularly in the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

and

bone formation Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in th ...

. As a member of the

basic helix-loop-helix Basic or BASIC may refer to: Science and technology * BASIC, a computer programming language * Basic (chemistry), having the properties of a base * Basic access authentication, in HTTP Entertainment * ''Basic'' (film), a 2003 film * Basic, one ...

(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 fun ...

, HES4 plays a crucial role in

T-cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...

development by responding to

Notch1 Neurogenic locus notch homolog protein 1 (Notch 1) is a protein encoded in humans by the ''NOTCH1'' gene. Notch 1 is a single-pass transmembrane receptor. Function This gene encodes a member of the Notch family. Members of this type 1 transm ...

signaling, which is vital for guiding hematopoietic progenitor cells toward becoming

T-cells T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...

. Additionally, HES4 has emerged as a significant factor in the context of

osteosarcoma An osteosarcoma (OS) or osteogenic sarcoma (OGS) is a cancerous tumor in a bone. Specifically, it is an aggressive malignant neoplasm that arises from primitive transformed cells of mesenchyme, mesenchymal origin (and thus a sarcoma) and that exhi ...

(OS), a type of

bone cancer A bone tumor is an neoplastic, abnormal growth of tissue in bone, traditionally classified as benign, noncancerous (benign) or malignant, cancerous (malignant). Cancerous bone tumors usually originate from a cancer in another part of the body su ...

, where its expression correlates with aggressive

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

behavior and poor patient prognosis.

Structure

Primary

HES4 is a

polypeptide chain Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ami ...

consisting of 221

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

with a

molecular weight A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...

of 23,523 Da.

Secondary

The secondary structure of the completed HES4 protein features a structural motif known as the

(bHLH). This motif is characterized by two

alpha helices An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...

connected by a loop, which allows for a compact and flexible structure. 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 Gene expression is the process (including its Regulation of gene expression, regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, ...

. In HES4, the basic region of the motif typically contains positively charged

that facilitate binding to specific DNA sequences, often in the context of

transcriptional regulation In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA ( transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from al ...

Function

Notch1 activation

HES4 plays an important role in the development of

, which are a type of

white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

that are a crucial part of the mammalian

. The process of

development starts when a signaling pathway called Notch1 is activated in certain blood precursor cells, known as hematopoietic progenitor cells.

activation is crucial for initiating

development while suppressing differentiation into other lineages. While the functions of these genes are well understood in

mice A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

, the absence of a mouse

for HES4 has made its role in humans less clear. When

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 Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...

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

. In contrast, HES4 also supports the early stages of

development but does not prevent the formation of

B-cells B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...

, another important type of immune cell. Together, HES4 and HES1 ensure that as blood precursor cells receive the

signal, so that they successfully start their journey to becoming T-cells.

Clinical significance

Because

play an important role in constantly scrutinizing and destroying

tumor cells A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

, and HES4 is important for the development of

in humans, it has been hypothesised to be an

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

and has been investigated using

human cell lines Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

and

Bone cancer

The clinical significance of HES4 in

(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 A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

, with a greater tendency to spread to other parts of the body. Interestingly, while overexpressing HES4 promotes aggressive tumor behavior by inhibiting the normal

bone cell An osteocyte, an oblate-shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide an ...

differentiation process, another

target gene, HES1, has opposing effects, where overexpression has a preventative effect on tumor growth.

References

{{Transcription factors and intracellular receptors, g1 Genes on human chromosome 1 Oncogenes