GATA3 is a
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 f ...
that in humans is encoded by the ''GATA3''
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 b ...
. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes.
The GATA3 transcription factor is critical for the embryonic development of various tissues as well as for
inflammatory and
humoral immune responses and the proper functioning of the
endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
of
blood vessels. GATA3 plays central role in allergy and immunity against worm infections. ''GATA3''
haploinsufficiency (i.e. loss of one or the two inherited ''GATA3'' genes) results in a
congenital disorder termed the
Barakat syndrome.
Current clinical and laboratory research is focusing on determining the benefits of directly or indirectly blocking the action of GATA3 in inflammatory and allergic diseases such as asthma.
It is also proposed to be a clinically important marker for various types of cancer, particularly those of the breast. However, the role, if any, of GATA3 in the development of these cancers is under study and remains unclear.
Gene
The ''GATA3'' gene is located close to the end of the short arm of chromosome 10 at position p14. It consists of 8
exons
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding seque ...
, and codes for two variants viz., GATA3, variant 1, and GATA3, variant 2. Expression of ''GATA3'' may be regulated in part or at times by the
antisense RNA
Antisense RNA (asRNA), also referred to as antisense transcript, natural antisense transcript (NAT) or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and ...
, GATA3-AS1, whose gene is located close to the ''GATA3'' gene on the short arm of chromosome 10 at position p14. Various types of
mutations including
point mutations as well as small- and large-scale
deletional mutations cause an
autosomal dominant genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
, the Barakat syndrome (also termed hypoparathyroidism, deafness, and renal dysplasia syndrome). The location of ''GATA3'' borders that of other critical sites on chromosome 10, particularly a site located at 10p14-p13. Mutations in this site cause the congenital disorder DiGeorge syndrome/velocardiofacial syndrome complex 2 (or DiGeorge syndrome 2). Large-scale deletions in ''GATA3'' may span into the DiGeorge syndrome 2 area and thereby cause a complex syndrome with features of the
Barakat syndrome combined with some of those of the DiGeorge syndrome 2.
Knockout of both ''GATA3'' genes in mice is fatal: these animals die at embryonic days 11 and 12 due to internal bleeding. They also exhibit gross deformities in the brain and spine as well as aberrations in fetal liver hematopoiesis.
Protein
GATA3 variant 1 is a
linear
Linearity is the property of a mathematical relationship ('' function'') that can be graphically represented as a straight line. Linearity is closely related to '' proportionality''. Examples in physics include rectilinear motion, the linear ...
protein consisting of 444
amino acids. GATA3 variant 2 protein is an identically structured
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some is ...
of, but 1 amino acid shorter than, GATA3 variant 1. Differences, if any, in the functions of these two variants have not been reported. With respect to the best studied variant, variant 1, but presumably also variant 2, one of the
zinc finger structural motifs, ZNF2, is located at the protein's
C-terminus and binds to specific
gene promoter
In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein ( mRNA), or can have a function in and ...
DNA sequences to regulate the expression of the genes controlled by these promoters. The other zinc finger, ZNF1, is at the protein's
N-terminus and interacts with various nuclear factors, including
Zinc finger protein 1 (i.e. ZFPM1, also termed Friends of GATA1
.e. FOG-1 and
ZFPM2 (i.e. FOG-2), that modulate GATA3's gene-stimulating actions.
Pathophysiology
The GATA3 transcription factor regulates the expression of genes involved in the development of various tissues as well as genes involved in
physiological
Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemica ...
as well as
pathological humoral inflammatory and allergic responses.
Function
GATA3 belongs to the
GATA family of
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 f ...
s.
Gene-deletion studies in mice indicate that ''Gata3'' (mouse gene equivalent to GATA3) is critical for the embryonic development and/or function of various cell types (e.g.
fat cells,
neural crest cells,
lymphocytes) and tissues (e.g. kidney, liver, brain, spinal cord, mammary gland).
Studies in humans implicate GATA3 in the following:
*1) GATA3 is required for the development of the
parathyroid gland, sensory components of the auditory system, and the kidney in animals and humans.
It may also contribute to the development of the vagina and uterus in humans.
*2) In humans, GATA3 is required for the development and/or function of
innate lymphoid cells (ILCs), particularly
Group 2 ILCs as well as for the development of
T helper cells,(Th cells), particularly
Th2 cells
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
. Group 2 ILCs and Th2 cells, and thereby GATA3, are critical for the development of allergic and
humoral immune responses in humans. Comparable studies in animals implicate GATA3 in the development of lymphocytes that mediate allergic and humoral immunity as well as allergic and humeral immune responses.
*3) GATA3 promotes the secretion of
IL-4,
IL-5, and
IL-13 from Th2 cells in humans and has similar actions on comparable mouse lymphocytes. All three of these interleukins serve to promote allergic responses,
*4) GATA3 induces the
maturation of precursor cells into
breast
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and sec ...
epithelial cells
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...
and maintains these cells in their mature state in mice and possibly humans.
*5) In mice, GATA3 is responsible for the normal development of various tissues including the skin, fat cells, the
thymus
The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or '' T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders ...
, and the nervous system.
Clinical significance
Mutations
Inactivating mutations in one of the two parental GATA3 genes cause the
congenital disorder of
hypoparathyroidism with
sensorineural deafness and
kidney malformations, i.e. the
Barakat syndrome. This rare syndrome may occur in families or as a new mutation in an individual from a family with no history of the disorder. Mutations in GATA3 cause variable degrees of hypoparathyroidism, deafness, and kidney disease
birth defects because of 1) individual differences in the
penetrance of the mutation, 2) a sporadic, and as yet unexplained, association with malformation of uterus and vagina, and 3) mutations which extend beyond the ''GATA3'' gene into chromosomal areas where mutations are responsible for developing other types of abnormalities which are characteristics of the DeGeorge syndrome 2. The Barakat syndrome is due to a
haploinsufficiency in GATA3 levels, i.e. levels of the transcription factor that are insufficient for the normal development of the cited tissues during
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 spe ...
.
Allergy
Mouse studies indicate that inhibiting the expression of GATA3 using
antisense RNA
Antisense RNA (asRNA), also referred to as antisense transcript, natural antisense transcript (NAT) or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and ...
methods suppresses allergic inflammation. The protein is overexpressed in the afflicted tissues of individuals with various forms of allergy including asthma, rhinitis, nasal polyps, and atopic eczema. This suggests that it may have a role in promoting these disorders.
In a
phase IIA clinical study of individuals suffering allergen-induced asthma, inhalation of
Deoxyribozyme
Deoxyribozymes, also called DNA enzymes, DNAzymes, or catalytic DNA, are DNA oligonucleotides that are capable of performing a specific chemical reaction, often but not always catalytic. This is similar to the action of other biological enzyme ...
ST010, which specifically inactivates GATA3
messenger RNA, for 28 days reduced early and late immune lung responses to inhaled allergen. The clinical benefit of inhibiting GATA3 in this disorder is thought to be due to interfering with the function of Group 2 ILCs and Th2 cells by, for example, reducing their production of IL-4, IL-13, and especially IL-5. Reduction in these
eosinophil-stimulating interleukins, it is postulated, reduces this cells ability to promote allergic reactivity and responses.
For similar reasons, this treatment might also prove to be clinical useful for treating other allergic disorders.
Tumors
Breast tumors
= Development
=
''GATA3'' is one of the three genes mutated in >10% of
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...
s (Cancer Genome Atlas).
Studies in mice indicate that the gene is critical for the normal development of breast tissue and directly regulates luminal cell (i.e. cells lining mammary ducts) differentiation in experimentally induced breast cancer.
Analytic studies of human breast cancer tissues suggest that ''GATA3'' is required for specific type of low risk breast cancer (i.e. luminal A), is integral to the expression of
estrogen receptor alpha, and (in estrogen receptor negative/androgen receptor positive cancers)
androgen receptor signaling.
These studies suggest that ''GATA3'' is involved in the development of at least certain types of breast cancer in humans. However, there is disagreement on this, with some studies suggesting that the expression of the ''GATA3'' acts to inhibit and other studies suggesting that it acts to promote the development, growth, and/or spread of this cancer. Further studies are needed to elucidate the role, if any, of GATA3 in the development of breast cancer.
= Marker
=
Immuocytochemical analysis of GATA3 protein in breast cells is a valuable marker for diagnosing primary breast cancer, being tested as positive in up to 94% of cases. It is especially valuable for estrogen receptor positive breast cancers but is less sensitive (435-66% elevated), although still more valuable than many other markers, for diagnosing
triple-negative breast cancer
Triple-negative breast cancer (TNBC) is any breast cancer that lacks or show low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification (i.e. the ...
s. This analysis is widely used as a clinically valuable marker for breast cancer.
Other tumor types
Similar to breast tumors, the role of ''GATA3'' in the genesis of other tumor types is unclear but detection of its transcription factor product may be diagnostically useful. Immuocytochemical analysis of GATA3 protein is considered a valuable marker for certain types of
urinary bladder and
urethral cancers as well as for
parathyroid gland tumors (cancerous or benign), Single series reports suggest that this analysis might also be of value for diagnosing
salivary gland tumor
Salivary gland tumours, also known as mucous gland adenomas or neoplasms, are tumours that form in the tissues of salivary glands. The salivary glands are classified as major or minor. The major salivary glands consist of the parotid, submandibul ...
s,
salivary duct carcinomas,
mammary analog secretory carcinomas, benign ovarian
Brenner tumors, benign
Walthard cell rests, and
paragangliomas.
Interactions
GATA3 has been shown to
interact
Advocates for Informed Choice, doing business as, 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 trai ...
with the following transcription factor regulators:
ZFPM1 and
ZFPM2;
LMO1;
and
FOXA1.
These regulators may promote or inhibit GATA3 in stimulating the expression of its target genes.
See also
*
GATA transcription factors
References
; Attribution
Further reading
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External links
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{{Transcription factors, g2
Transcription factors