GATA-3 Dose-Dependent Checkpoints in Early T Cell Commitment

Scripture-Adams, Deirdre D.; Damle, Sagar S.; Li, Long; Elihu, Koorosh J.; Qin, Shuyang S.; Arias, Alexandra M.; Butler, Robert R.; Champhekar, Ameya S.; Zhang, Jingli A.; Rothenberg, Ellen V.

doi:10.4049/jimmunol.1301663

Cited by 72 publications

(135 citation statements)

References 56 publications

Supporting

Mentioning

127

Contrasting

Order By: Relevance

“…4A). One of these genes is Cpa3 (150% change compared to the wild type), a mast cell gene, which is also induced when excess GATA3 is retrovirally expressed in DN1/DN2 stage T cells (40) and which is downregulated by GATA3 short hairpin RNA (shRNA) knockdown of DN2 stage T cells (33). Gene ontology analysis using the DAVID functional annotation tool (41) (https://david.ncifcrf.gov/) highlighted the most significant changes in genes related to the chromosome/histone, the cell cycle, and kinetochore organization in the 126 downregulated genes (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Proplatelet formation is inhibited after either diminished or excessive expression of the transcription factor MafG in megakaryocytes (67), and T cell development in the thymus is blocked when there is either too little or too much GATA3 (32,33,40,68,69). Of note in this regard, the inactivation of one Gata3 allele often results in a mild reduction in T cell development in humans (HDR [hypoparathyroidism, deafness, and renal dysplasia] syndrome) (70)(71)(72) and in mice (49), while a 2-fold increase in the GATA3 protein abundance has been shown to induce T cell lymphoma (73).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

Sekiguchi

Panwar

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

Allelic exclusion describes the essential immunological process by which feedback repression of sequential DNA rearrangements ensures that only one autosome expresses a functional T or B cell receptor. In wild-type mammals, approximately 60% of cells have recombined the DNA of one T cell receptor ␤ (TCR␤) V-to-DJ-joined allele in a functional configuration, while the second allele has recombined only the DJ sequences; the other 40% of cells have recombined the V to the DJ segments on both alleles, with only one of the two alleles predicting a functional TCR␤ protein. Here we report that the transgenic overexpression of GATA3 leads predominantly to biallelic TCR␤ gene (Tcrb) recombination. We also found that wild-type immature thymocytes can be separated into distinct populations based on intracellular GATA3 expression and that GATA3 LO cells had almost exclusively recombined only one Tcrb locus (that predicted a functional receptor sequence), while GATA3 HI cells had uniformly recombined both Tcrb alleles (one predicting a functional and the other predicting a nonfunctional rearrangement). These data show that GATA3 abundance regulates the recombination propensity at the Tcrb locus and provide new mechanistic insight into the historic immunological conundrum for how Tcrb allelic exclusion is mediated.KEYWORDS allelic exclusion, T cell receptor beta locus, GATA3, monoallelic-tobiallelic switch O ne enduring mystery in cellular immunology regards the underlying mechanisms that control antigen receptor allelic exclusion (1, 2), the process whereby B or T lymphocytes are programmed to express only one functional allele for each chain of their respective antigen receptors (B cell receptor [BCR] or T cell receptor [TCR]), thus avoiding the coexistence of multiple antigen specificities in a single immune cell. Lymphocytes acquire the diversity of antigen recognition (3) as well as a unique monospecificity for particular antigens (4) during development in the bone marrow (B cells) or the thymus (T cells).T lymphocyte development is generally characterized by division into multiple stages based on developmental timing and the location and expression of specific cell surface markers (5). T cell development begins when multipotential hematopoietic progenitor cells in the bone marrow migrate through the bloodstream to the thymus, where early T lineage progenitors (ETPs) are generated and later specified to become T cells (6-10). ETPs differentiate into double-negative (DN) cells (DN2 to DN4 stages) that express neither the CD4 nor the CD8 coreceptor, then into double-positive (DP)

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

Sekiguchi

Panwar

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…This balance is tipped during commitment, with the silencing of the phase 1 regulatory genes and down-regulation of Kit, but only limited aspects of this process are understood. GATA-3, Runx1, and TCF-1 (or its relative LEF-1) eventually play roles in silencing expression of phase 1 regulatory genes encoding PU.1 and Bcl11a during commitment, as demonstrated by gain-and loss-offunction data (27,(36)(37)(38)(39) (Fig. 1B).…”

Section: T-cell Specification Grn Transitions At Commitment: a Distinctmentioning

confidence: 90%

“…This updated model incorporates recent data on functional impacts of E2A (22), on PU.1 and its interactions with Notch, Myb, and GATA-3 (21,23,24), on Notch blockade of the myeloid program via Hes1 against Cebpa (25, 26), on GATA-3 and its mutual antagonism with the B-cell program (27)(28)(29)(30), and on positive regulators of Bcl11b itself (1,31). Discussed in detail in SI Appendix, Supplementary Text, these results reveal two major switch circuits.…”

Section: T-cell Specification Grn Transitions At Commitment: a Distinctmentioning

confidence: 99%

“…Notch signaling selectively intervenes in their actions to prevent alternative lineage specification (21,26,34,35), but still allows PU.1 to sustain lymphoid-compatible phase 1 regulatory genes like Bcl11a, Lmo2, and Mef2c (21) in phase 1 pro-T cells. Gene regulation at this stage can also reflect balances between different factors competing to regulate common targets: for example, PU.1 and GATA-3 may compete, respectively, to repress or activate Zfpm1, and Ets1, and to activate or repress Bcl11a (21,23,27). This balance is tipped during commitment, with the silencing of the phase 1 regulatory genes and down-regulation of Kit, but only limited aspects of this process are understood.…”

Section: T-cell Specification Grn Transitions At Commitment: a Distinctmentioning

confidence: 99%

See 1 more Smart Citation

Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

Longabaugh

Zeng

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

148

View full text Add to dashboard Cite

T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms.

show abstract

Notch in Leukemia

McCarter

Wang

Chiang

2018

Advances in Experimental Medicine and Biology

View full text Add to dashboard Cite

Notch is commonly activated in lymphoid malignancies through ligand-independent and ligand-dependent mechanisms. In T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), ligand-independent activation predominates. Negative Regulatory Region (NRR) mutations trigger supraphysiological Notch1 activation by exposing the S2 site to proteolytic cleavage in the absence of ligand. Subsequently, cleavage at the S3 site generates the activated form of Notch, intracellular Notch (ICN). In contrast to T-ALL, in mature lymphoid neoplasms such as chronic lymphocytic leukemia (CLL), the S2 cleavage site is exposed through ligand-receptor interactions. Thus, agents that disrupt ligand-receptor interactions might be useful for treating these malignancies. Notch activation can be enhanced by mutations that delete the C-terminal proline (P), glutamic acid (E), serine (S), and threonine (T) (PEST) domain. These mutations do not activate the Notch pathway per se, but rather impair degradation of ICN. In this chapter, we review the mechanisms of Notch activation and the importance of Notch for the genesis and maintenance of lymphoid malignancies. Unfortunately, targeting the Notch pathway with pan-Notch inhibitors in clinical trials has proven challenging. These clinical trials have encountered dose-limiting on-target toxicities and primary resistance. Strategies to overcome these challenges have emerged from the identification and improved understanding of direct oncogenic Notch target genes. Other strategies have arisen from new insights into the "nuclear context" that selectively directs Notch functions in lymphoid cancers. This nuclear context is created by factors that co-bind ICN at cell-type specific transcriptional regulatory elements. Disrupting the functions of these proteins or inhibiting downstream oncogenic pathways might combat cancer without the intolerable side effects of pan-Notch inhibition.

show abstract

GATA-3 Dose-Dependent Checkpoints in Early T Cell Commitment

Cited by 72 publications

References 56 publications

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

Notch in Leukemia

Contact Info

Product

Resources

About