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Event: 1711

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Induction of GATA3 expression

Short name

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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

Organ term
immune system

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Binding to ER-α leading to exacerbation of SLE	KeyEvent	Yasuharu Otsubo (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
All life stages

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Mixed

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Naïve CD4 T cells can differentiate into several different types of T helpers, and Th2 cells, capable of producing IL-4, IL-5 and IL-13, are involved in humoral immunity against extracellular pathogens and in the induction of asthma and other allergic diseases. It was reported that GATA-3 promotes Th2 responses through three different mechanisms (Zhu J. 2006). Cell fate determination in each lineage requires at least two types of transcription factors: the master regulators (GATA3) as well as the signal transducers and activator of transcription (STAT) proteins (Zhu J. 2010). A direct role in bridging distant regulatory elements has been demonstrated for GATA3 at Th2 cytokine loci (Spilianakis and Flavell, 2004). GATA3 is the Th2 master regulator (Zhu J．2010, Sung-Yun. 2004, Zhu J. 2004, Zheng W. 1997, Zhang DH. 1997), but it also plays important roles in multiple steps of CD4 T cell development (Ho IC. 2009). GATA3 can act as pioneer factors by initiating local chromatin opening and allowing the recruitment of other transcription factors to regulatory elements (Spilianakis and Flavell, 2004). Th2 differentiation is completely abolished both in vitro and in vivo when GATA3 is conditionally deleted in peripheral CD4 T cells (Zhu J. 2004, Pai SY. 2004). GATA-3 mRNA expression also increased in patients with SLE, compared with the healthy control groups (Zheng H. 2015, Sonia GR. 2012).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

GATA3 mRNA in CD4 T cells can be detected by Real-time PCR (RT-PCR) (Lambert KC. 2005, Kurata H. 1999, Zhu J. 2001).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Involvement of GATA3 in Th2 cell development through ER is common in humans, rodents, and other mammalian species (Ho IC. 2009). protein sequence conservation between all six vertebrate members (mouse, human, dog, cow, armadillo, capuchin and opossum) identifies GATA3 as having the highest sequence similarity with both its GATA paralogs and orthologs, suggesting that it may be closest to the ancestral mammalian GATA factor (Tremblay M. 2018).

References

List of the literature that was cited for this KE description. More help

Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol. 2010; 28:445-89.
Spilianakis CG & Flavell RA, Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nature Immunology. 2004; 5: 1017-1027.
Zhu J, Paul WE. Peripheral CD4 T cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev. 2010; 238(1):247-62.
Sung-Yun, Morgan L. T. I-Cheng H. (2004). GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells. Proceedings of the National Academy of Sciences. 101 (7): 1993-1998.
Zhu J, Min B, Paul WE, et al. Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat Immunol. 2004;5(11):1157-65.
Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997. 16;89(4):587-96.
Zhang DH, Cohn L, Ray P, Bottomly K, Ray A. Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem. 1997. 22;272(34):21597-603.
Ho IC, Tai TS, Pai SY. GATA3 and the T-cell lineage: essential functions before and after Thelper-2-cell differentiation. Nat Rev Immunol. 2009;9(2):125-35.
Zheng H, Guo X, Zhu Y, et al., Distinct role of Tim-3 in systemic lupus erythematosus and clear cell renal cell carcinoma. Int J Clin Exp Med 2015;8(5):7029-7038.
Sonia GR, et al. Altered AKT1 and MAPK1 Gene Expression on Peripheral Blood Mononuclear Cells and Correlation with T-Helper-Transcription Factors in Systemic Lupus Erythematosus Patients. Mediators of Inflammation 2012, Article ID 495934
Lambert KC, Curran EM, et al. Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation. J Immunol. 2005; 175(9): 5716-23.
Kurata, H., Lee, H. J., O’Garra, A. and Arai, N. (1999). Ectopic expression of activated STAT6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells. Immunity 11: 677-688.
Zhu, J., Guo, L., Watson, C. J., Hu-Li, J. and Paul, W. E. (2001). STAT6 is necessary and sufficient for IL-4's role in Th2 differentiation and cell expansion. The Journal of Immunology 166(12): 7276-7281.
Tremblay M, GATA transcription factors in development and disease. 2018; 22:145(20).
Guo H, Liu T, Ling F, et al. Bisphenol A in combination with TNF-alpha selectively induces Th2 cell-promoting dendritic cells in vitro with an estrogen-like activity. Cell Mol Immunol. 2010;7(3):227-34.