ILC2 development requires GATA3-related super-enhancers after lineage commitment
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ABSTRACT:
PROVIDER: PRJNA902420 | ENA |
REPOSITORIES: ENA
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Project description:This SuperSeries is composed of the SubSeries listed below. Group 2 innate lymphoid cells (ILC2) are a subset of innate lymphocytes that produce type 2 cytokines, including IL-4, IL-5, and IL-13. GATA3 being a critical transcription factor for ILC2 development at multiple stages. However, when and how GATA3 is induced to the levels required for ILC2 development remains elusive. Herein, we identified ILC2-specific tandem GATA3-related super-enhancers (G3SE) that induce high GATA3 in ILC2-committed precursors. G3SE-deficient mice exhibit ILC2 loss in the BM, lung, liver, and small intestine, a slight ILC1 increase, and no difference in ILC3, LTi, NK cells, nor Th2 cells. Single-cell RNA-sequencing revealed that GATA3 induction in late ILC2-committed precursors depends on G3SEs and is required for the transition to mature ILC2. Cnot6l, part of the CCR4-Not deadenylase complex, is a possible GATA3 target during ILC2 development. Our findings indicate a novel regulatory mechanism for GATA3 expression during ILC2 development.
2024-05-14 | GSE218155 | GEO
Project description:The stepwise conversion of multipotent precursors into committed T-cell progenitors depends on several transcriptional regulators, but the interplay between these factors is still obscure. This is particularly true in human since the core early Notch signalling pathway also supports NK cell development and requires tight regulation for efficient T-lineage commitment and differentiation. Here, we show that GATA3, in contrast to TCF1, induces T-lineage commitment following NOTCH1-induced T-lineage specification through direct regulation of at least 3 distinct processes: repression of NK-cell fate, activation of T-lineage genes to promote further differentiation, and downmodulation of Notch signalling activity. GATA3-mediated repression of the NOTCH1 target gene DTX1 hereby is essential to induce T-lineage commitment at the expense of NK cell differentiation. Thus, human T-lineage commitment is dependent on the precise collaboration of several transcriptional regulators that integrate through both positive and negative regulatory loops. ChIP-sequencing data was generated for GATA3 in human thymocytes
2016-04-06 | E-GEOD-71751 | biostudies-arrayexpress
Project description:The type 2 helper effector program is driven by the master transcription factor GATA3 and can be expressed by subsets of both innate lymphoid cells (ILCs) and adaptive CD4+ T helper (Th) cells. While ILC2s and Th2 cells acquire their type 2 differentiation program under very different contexts, the distinct regulatory mechanisms governing this common program are only partially understood. Here we show that the differentiation of ILC2s, and their concomitant high level of GATA3 expression, are controlled by a Gata3 enhancer, Gata3 +674/762, that plays only a minimal role in Th2 cell differentiation. Mice lacking this enhancer exhibited defects in several but not all type 2 inflammatory responses, depending on the respective degree of ILC2 and Th2 cell involvement. Our study provides molecular insights into the different gene regulatory pathways leading to the acquisition of the GATA3-driven type 2 helper effector program in innate and adaptive lymphocytes.
2021-07-22 | GSE169542 | GEO
Project description:The stepwise conversion of multipotent precursors into committed T-cell progenitors depends on several transcriptional regulators, but the interplay between these factors is still obscure. This is particularly true in human since the core early Notch signalling pathway also supports NK cell development and requires tight regulation for efficient T-lineage commitment and differentiation. Here, we show that GATA3, in contrast to TCF1, induces T-lineage commitment following NOTCH1-induced T-lineage specification through direct regulation of at least 3 distinct processes: repression of NK-cell fate, activation of T-lineage genes to promote further differentiation, and downmodulation of Notch signalling activity. GATA3-mediated repression of the NOTCH1 target gene DTX1 hereby is essential to induce T-lineage commitment at the expense of NK cell differentiation. Thus, human T-lineage commitment is dependent on the precise collaboration of several transcriptional regulators that integrate through both positive and negative regulatory loops. Gene expression was profiled in CT CD34+ cells after transduction with control or GATA3 and coculture on OP9-DL1 for 48h. Cells were collected 48h after coculture and sorted for CD45+EGFP+. 3 independent experiments were performed on 3 different thymus donors.
2016-04-06 | E-GEOD-71752 | biostudies-arrayexpress
Project description:A Gata3 enhancer necessary for ILC2 development and function
| PRJNA716999 | ENA
Project description:Group 2 innate lymphoid cells (ILC2s) orchestrate tissue homeostasis, allergic disorders and anti-helminth protective immunity through their production of cytokines. However, their rarity has hampered high-throughput genetic screening approaches to uncover novel ILC2 regulators in an unbiased manner. We combined expansion of progenitors from multi-reporter mouse strains with optimised ILC differentiation cultures to perform CRISPR-Cas9 screens for regulators of ILC2 development and function. Mef2d emerged as a critical regulator of GATA3 and IL-13, and was essential for type-2 immunity as demonstrated by conditional Mef2d-deficient mice, including a Boolean-ILC2-Cre (BIC) mouse strain developed to enable ILC2-specific gene deletion. Mechanistically, Mef2d bound and transcriptionally repressed the Zc3h12a locus encoding the endonuclease Regnase-1, a negative regulator of IL-33 receptor (ST2) and GATA3 expression, thereby promoting IL-33-mediated ILC2 proliferation and cytokine production. Notably, in ILC2s Mef2d also acted downstream of leukotriene C4-induced calcium-mediated signalling to translocate NFAT1 to the nucleus to promote type-2 gene transcription. These Mef2d-mediated pathways converge and feedback to potentiate type-2 immunity.
2024-07-03 | GSE242146 | GEO
Project description:Group 2 innate lymphoid cells (ILC2s) orchestrate tissue homeostasis, allergic disorders and anti-helminth protective immunity through their production of cytokines. However, their rarity has hampered high-throughput genetic screening approaches to uncover novel ILC2 regulators in an unbiased manner. We combined expansion of progenitors from multi-reporter mouse strains with optimised ILC differentiation cultures to perform CRISPR-Cas9 screens for regulators of ILC2 development and function. Mef2d emerged as a critical regulator of GATA3 and IL-13, and was essential for type-2 immunity as demonstrated by conditional Mef2d-deficient mice, including a Boolean-ILC2-Cre (BIC) mouse strain developed to enable ILC2-specific gene deletion. Mechanistically, Mef2d bound and transcriptionally repressed the Zc3h12a locus encoding the endonuclease Regnase-1, a negative regulator of IL-33 receptor (ST2) and GATA3 expression, thereby promoting IL-33-mediated ILC2 proliferation and cytokine production. Notably, in ILC2s Mef2d also acted downstream of leukotriene C4-induced calcium-mediated signalling to translocate NFAT1 to the nucleus to promote type-2 gene transcription. These Mef2d-mediated pathways converge and feedback to potentiate type-2 immunity.
2024-07-03 | GSE242030 | GEO
Project description:Group 2 innate lymphoid cells (ILC2s) orchestrate tissue homeostasis, allergic disorders and anti-helminth protective immunity through their production of cytokines. However, their rarity has hampered high-throughput genetic screening approaches to uncover novel ILC2 regulators in an unbiased manner. We combined expansion of progenitors from multi-reporter mouse strains with optimised ILC differentiation cultures to perform CRISPR-Cas9 screens for regulators of ILC2 development and function. Mef2d emerged as a critical regulator of GATA3 and IL-13, and was essential for type-2 immunity as demonstrated by conditional Mef2d-deficient mice, including a Boolean-ILC2-Cre (BIC) mouse strain developed to enable ILC2-specific gene deletion. Mechanistically, Mef2d bound and transcriptionally repressed the Zc3h12a locus encoding the endonuclease Regnase-1, a negative regulator of IL-33 receptor (ST2) and GATA3 expression, thereby promoting IL-33-mediated ILC2 proliferation and cytokine production. Notably, in ILC2s Mef2d also acted downstream of leukotriene C4-induced calcium-mediated signalling to translocate NFAT1 to the nucleus to promote type-2 gene transcription. These Mef2d-mediated pathways converge and feedback to potentiate type-2 immunity.
2024-07-03 | GSE262028 | GEO
Project description:The stepwise conversion of multipotent precursors into committed T-cell progenitors depends on several transcriptional regulators, but the interplay between these factors is still obscure. This is particularly true in human since the core early Notch signalling pathway also supports NK cell development and requires tight regulation for efficient T-lineage commitment and differentiation. Here, we show that GATA3, in contrast to TCF1, induces T-lineage commitment following NOTCH1-induced T-lineage specification through direct regulation of at least 3 distinct processes: repression of NK-cell fate, activation of T-lineage genes to promote further differentiation, and downmodulation of Notch signalling activity. GATA3-mediated repression of the NOTCH1 target gene DTX1 hereby is essential to induce T-lineage commitment at the expense of NK cell differentiation. Thus, human T-lineage commitment is dependent on the precise collaboration of several transcriptional regulators that integrate through both positive and negative regulatory loops.
2016-04-06 | GSE71752 | GEO
Project description:The stepwise conversion of multipotent precursors into committed T-cell progenitors depends on several transcriptional regulators, but the interplay between these factors is still obscure. This is particularly true in human since the core early Notch signalling pathway also supports NK cell development and requires tight regulation for efficient T-lineage commitment and differentiation. Here, we show that GATA3, in contrast to TCF1, induces T-lineage commitment following NOTCH1-induced T-lineage specification through direct regulation of at least 3 distinct processes: repression of NK-cell fate, activation of T-lineage genes to promote further differentiation, and downmodulation of Notch signalling activity. GATA3-mediated repression of the NOTCH1 target gene DTX1 hereby is essential to induce T-lineage commitment at the expense of NK cell differentiation. Thus, human T-lineage commitment is dependent on the precise collaboration of several transcriptional regulators that integrate through both positive and negative regulatory loops.
2016-04-06 | GSE71751 | GEO