Heart- and neural crest derivatives-expressed protein 2 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 in humans is encoded by the ''HAND2''

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 ...

Function

The protein encoded by this gene belongs to the

basic helix-loop-helix BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Thomas E. Kurtz at Dartmouth College ...

family of transcription factors. This gene product is one of two closely related family members, the HAND proteins

Hand1 Heart- and neural crest derivatives-expressed protein 1 is a protein that in humans is encoded by the ''HAND1'' gene. A member of the HAND subclass of basic Helix-loop-helix (bHLH) transcription factors, the Heart and neural crest-derived transc ...

and Hand2, which are asymmetrically expressed in the developing ventricular chambers and play an essential role in cardiac morphogenesis. Working in a complementary fashion, they function in the formation of the

right ventricle A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the upper ...

and

aortic arch The aortic arch, arch of the aorta, or transverse aortic arch () is the part of the aorta between the ascending and descending aorta. The arch travels backward, so that it ultimately runs to the left of the trachea. Structure The aorta begins a ...

arteries, implicating them as mediators of congenital heart disease. In addition, this transcription factor plays an important role in limb and branchial arch development. In one study, it was found that a

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

of the Hand2 protein in patients with the

congenital heart disease A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...

(CHD)

Tetralogy of Fallot Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. Classically, the four defects are: *pulmonary stenosis, which is narrowing of the exit from the ri ...

experienced significantly decreased Hand2 interactions with other key developmental genes such as

GATA4 Transcription factor GATA-4 is a protein that in humans is encoded by the ''GATA4'' gene. Function This gene encodes a member of the GATA family of zinc finger transcription factors. Members of this family recognize the GATA motif which is pr ...

and NKX2.5. Hand2 mutations have the potential to be genes for the future study of right ventricle stenosis and its pathogenesis. In

avian Avian may refer to: *Birds or Aves, winged animals *Avian (given name) (russian: Авиа́н, link=no), a male forename Aviation *Avro Avian, a series of light aircraft made by Avro in the 1920s and 1930s *Avian Limited, a hang glider manufacture ...

species, Hand2 has been shown to be expressed in developing gut tissue and is believed to contribute to the formation of enteric neurons. Hand2 also plays a critical role in the establishment of a proper implantation environment for pregnancy in mice. The induction of Hand2 by

progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...

-dependent mechanisms in

uterine The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the hollow organ, organ in the female reproductive system, reproductive system of most female mammals, including humans that accommodates the embryonic development, embryonic an ...

stromal tissue suppresses

fibroblast growth factor Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in the ...

s (FGFs) that would otherwise stimulate

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...

producing pathways and impair

embryo implantation Implantation (nidation) is the stage in the embryonic development of Placental mammal, mammals in which the blastocyst hatches as the embryo, adheres, and invades into the wall of the female's uterus. Implantation is the first stage of gestation, ...

. Hand2 plays a role in lower jaw formation and tongue morphogenesis in mice by suppressing the homeobox genes

Dlx5 Homeobox protein DLX-5 is a protein that in humans is encoded by the distal-less homeobox 5 gene, or ''DLX5'' gene. DLX5 is a member of DLX gene family. Function This gene encodes a member of a homeobox transcription factor gene family simil ...

and

Dlx6 Homeobox protein DLX-6 is a protein that in humans is encoded by the ''DLX6'' gene. This gene encodes a member of a homeobox transcription factor gene family similar to the Drosophila ''Drosophila'' () is a genus of flies, belonging to the f ...

Interactions

HAND2 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

, NKX2.5,

PPP2R5D Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform is an enzyme that in humans is encoded by the ''PPP2R5D'' gene. Mutations in ''PPP2R5D'' cause Jordan's Syndrome. Function The product of this gene belongs to the ph ...

PHOX2A Paired mesoderm homeobox protein 2A is a protein that in humans is encoded by the ''PHOX2A'' gene. Function The protein encoded by this gene contains a paired-like homeodomain most similar to that of the Drosophila aristaless gene product. T ...

TWIST1 Twist-related protein 1 (TWIST1) also known as class A basic helix–loop–helix protein 38 (bHLHa38) is a basic helix-loop-helix transcription factor that in humans is encoded by the ''TWIST1'' gene. Function Basic helix-loop-helix (bHLH) tr ...

, and

TWIST2 Twist-related protein 2 is a protein that in humans is encoded by the ''TWIST2'' gene. The protein encoded by this gene is a basic helix-loop-helix (bHLH) transcription factor and shares similarity with another bHLH transcription factor, TWIST1. ...

Clinical significance

Hand2 interactions with

and

genes are critical for proper limb development. Recent literature shows over dosage of Hand2 can result in many defects in the limbs, face, heart, and lower lumbar vertebrae. In this instance, trisomy of the hand2 gene can directly cause human congenital heart disease. Hand2 gene

hypermethylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...

and

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 ...

silencing has also been implicated to increase the development of

endometrial The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional layer ...

cancer. Mounting evidence showing its methylation increased chances of premalignant endometrial lesions. Hand2, in addition to its other functions in the developing heart and limbs, has been found to be an important

transcription factor 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 fu ...

seen in the endometrial stroma. In fact, in mice with the Hand2 gene knocked out, they developed premalignant lesions as they grew older, further providing evidence of its role in endometrial cancer development. These findings have led to Hand2 becoming a potentially promising

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

for early detection of endometrial cancer and may be used to predict its treatment.

Regulation of Hand2

HAND2 is an important transcription factor in development of the endothelial to

mesenchymal Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every o ...

transition (EMT) which allows for the development of the cardiac cushion in the atrioventricular canal which forms the mitral and tricuspid valves. The Hand2 gene regulatory network contains many genes that function in the EMT process, most notably Snail1, whose expression is lost if Hand2 is deficient. Since HAND2 is essential for separation of the atria and ventricles, a mutation in this gene has been linked to ventricular septal defects. Deficiency in HAND2 is only partially replaced by SNAIL1. The expression of Hand2 is regulated by an upstream long non-coding RNA called Upperhand (Uph) that is needed for RNA polymerase II to transcribe Hand2. If Uph is not present, then there is a decrease in the expression of Hand2 and thus a decrease in cardiac development. When Uph was knocked out, the right ventricular chamber did not develop and had a similar phenotype as when Hand2 is knocked out. In addition, Hand2 expression was absent in the atria, ventricles, and outflow tract of the heart and was reduced in the brachial arches and limb buds.

References

External links