GATA2 regulates mast cell identity and responsiveness to antigenic stimulation by promoting chromatin remodeling at super-enhancers

AbstractMast cells are critical effectors of allergic inflammation and protection against parasitic infections. We previously demonstrated that transcription factors GATA2 and MITF are the mast cell lineage-determining factors. However, it is unclear whether these lineage-determining factors regulate chromatin accessibility at mast cell enhancer regions. In this study, we demonstrate that GATA2 promotes chromatin accessibility at the super-enhancers of mast cell identity genes and primes both typical and super-enhancers at genes that respond to antigenic stimulation. We find that the number and densities of GATA2- but not MITF-bound sites at the super-enhancers are several folds higher than that at the typical enhancers. Our studies reveal that GATA2 promotes robust gene transcription to maintain mast cell identity and respond to antigenic stimulation by binding to super-enhancer regions with dense GATA2 binding sites available at key mast cell genes.

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GATA2 regulates mast cell identity and responsiveness to antigenic stimulation by promoting chromatin remodeling at super-enhancers

10.1101/2020.09.16.300327 ◽

2020 ◽

Author(s):

Yapeng Li ◽

Junfeng Gao ◽

Mohammad Kamran ◽

Laura Harmacek ◽

Thomas Danhorn ◽

...

Keyword(s):

Mast Cell ◽

Transcription Factors ◽

Chromatin Remodeling ◽

Binding Sites ◽

Allergic Inflammation ◽

Chromatin Accessibility ◽

Antigenic Stimulation ◽

Parasitic Infections ◽

Super Enhancer ◽

Determining Factors

AbstractMast cells (MCs) are critical effectors of allergic inflammation and protection against parasitic infections. We previously demonstrated that transcription factors GATA2 and MITF are the MC lineage-determining factors (LDTFs). However, it is unclear whether these LDTFs regulate chromatin accessibility at MC enhancer regions. In this study, we demonstrate that GATA2 promotes chromatin accessibility at the super-enhancers of MC identity genes and primes both typical and super-enhancers at genes that respond to antigenic stimulation. We found that the number and densities of GATA2-but not MITF-bound sites at the super-enhancers were several folds higher than that at the typical enhancers. Our studies revealed that GATA2 promotes robust gene transcription to maintain MC identity and respond to antigenic stimulation by binding to super-enhancer regions with dense GATA2 binding sites available at key MC genes.

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Core transcription regulatory circuitry orchestrates corneal epithelial homeostasis

Nature Communications ◽

10.1038/s41467-020-20713-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Mingsen Li ◽

Huaxing Huang ◽

Lingyu Li ◽

Chenxi He ◽

Liqiong Zhu ◽

...

Keyword(s):

Stem Cell ◽

Regulatory Networks ◽

Adult Stem Cell ◽

Chromatin Accessibility ◽

Transcriptional Regulatory Networks ◽

Cell Identity ◽

Corneal Epithelial ◽

Epithelial Homeostasis ◽

Super Enhancer ◽

Transcriptional Regulatory

AbstractAdult stem cell identity, plasticity, and homeostasis are precisely orchestrated by lineage-restricted epigenetic and transcriptional regulatory networks. Here, by integrating super-enhancer and chromatin accessibility landscapes, we delineate core transcription regulatory circuitries (CRCs) of limbal stem/progenitor cells (LSCs) and find that RUNX1 and SMAD3 are required for maintenance of corneal epithelial identity and homeostasis. RUNX1 or SMAD3 depletion inhibits PAX6 and induces LSCs to differentiate into epidermal-like epithelial cells. RUNX1, PAX6, and SMAD3 (RPS) interact with each other and synergistically establish a CRC to govern the lineage-specific cis-regulatory atlas. Moreover, RUNX1 shapes LSC chromatin architecture via modulating H3K27ac deposition. Disturbance of RPS cooperation results in cell identity switching and dysfunction of the corneal epithelium, which is strongly linked to various human corneal diseases. Our work highlights CRC TF cooperativity for establishment of stem cell identity and lineage commitment, and provides comprehensive regulatory principles for human stratified epithelial homeostasis and pathogenesis.

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The Clusters of Transcription Factors NFATC2, STAT5, GATA2, AP1, RUNX1 and EGR2 Binding Sites at the Induced Il13 Enhancers Mediate Il13 Gene Transcription in Response to Antigenic Stimulation

10.1101/2020.09.29.318618 ◽

2020 ◽

Author(s):

Mohammad Kamran ◽

Jinyi Liang ◽

Bing Liu ◽

Yapeng Li ◽

Junfeng Gao ◽

...

Keyword(s):

Mast Cells ◽

Gene Transcription ◽

Binding Sites ◽

Critical Role ◽

Allergic Inflammation ◽

Lysine Residue ◽

Antigenic Stimulation ◽

Biological Processes ◽

Ige Receptor ◽

Histone 3

AbstractInterleukin-13 plays a critical role in mediating many biological processes responsible for allergic inflammation. Mast cells express Il13 mRNA and produce IL-13 protein in response to antigenic stimulation. Enhancers are essential in promoting gene transcription and are thought to activate transcription by delivering essential accessory co-factors to the promoter to potentiate gene transcription. However, enhancers mediating Il13 have not been identified. Furthermore, which Il13 enhancers detect signals triggered by antigenic stimulation have not yet been defined. In this study, we identified potential Il13 enhancers using histone modification monomethylation at lysine residue 4 on histone 3 (H3K4me1) ChIP-seq and acetylation at lysine residue 27 on histone 3 (H3K27ac) ChIP-seq. We used Omni-ATAC-seq to determine which accessible regions within the potential Il13 enhancers that responded to IgE receptor crosslinking. We also demonstrated that the transcription factor (TF) cluster consisting of the NFATC2, STAT5, GATA2, AP1, and RUNX1 binding sites at the proximal Il13 enhancer, the TF cluster consisting of the EGR2-binding site at the distal Il13 E+6.5 enhancer, are critical in sensing the signals triggered by antigenic stimulation. Those enhancers, which are responsive to antigenic stimulation and constitutively active, cooperate to generate greater transcriptional outputs. Our study reveals a novel mechanism underlying how antigenic stimulation induces robust Il13 mRNA expression in mast cells.

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Faculty Opinions recommendation of Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1088774.550847 ◽

2007 ◽

Author(s):

Cornelis Murre

Keyword(s):

Transcription Factor ◽

Mast Cell ◽

T Cell ◽

Cell Lineage

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Myelomastocytic leukemia: myeloid neoplasm characterized by partial differentiation of mast cell-lineage cells

The Hematology Journal ◽

10.1038/sj.thj.6200164 ◽

2002 ◽

Vol 3 (2) ◽

pp. 90-94 ◽

Cited By ~ 42

Author(s):

Peter Valent ◽

Puchit Samorapoompichit ◽

Wolfgang R Sperr ◽

Hans-Peter Horny ◽

Klaus Lechner

Keyword(s):

Mast Cell ◽

Cell Lineage ◽

Partial Differentiation ◽

Myeloid Neoplasm

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Selective deletion of SHIP-1 in hematopoietic cells in mice leads to severe lung inflammation involving ILC2 cells

Scientific Reports ◽

10.1038/s41598-021-88677-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xujun Ye ◽

Fengrui Zhang ◽

Li Zhou ◽

Yadong Wei ◽

Li Zhang ◽

...

Keyword(s):

Lung Inflammation ◽

Airway Remodeling ◽

Pulmonary Inflammation ◽

Hematopoietic Cells ◽

Cell Lineage ◽

Allergic Inflammation ◽

Cell Types ◽

Lymphoid Cells ◽

Whole Body

AbstractSrc homology 2 domain–containing inositol 5-phosphatase 1 (SHIP-1) regulates the intracellular levels of phosphotidylinositol-3, 4, 5-trisphosphate, a phosphoinositide 3–kinase (PI3K) product. Emerging evidence suggests that the PI3K pathway is involved in allergic inflammation in the lung. Germline or induced whole-body deletion of SHIP-1 in mice led to spontaneous type 2-dominated pulmonary inflammation, demonstrating that SHIP-1 is essential for lung homeostasis. However, the mechanisms by which SHIP-1 regulates lung inflammation and the responsible cell types are still unclear. Deletion of SHIP-1 selectively in B cells, T cells, dendritic cells (DC) or macrophages did not lead to spontaneous allergic inflammation in mice, suggesting that innate immune cells, particularly group 2 innate lymphoid cells (ILC2 cells) may play an important role in this process. We tested this idea using mice with deletion of SHIP-1 in the hematopoietic cell lineage and examined the changes in ILC2 cells. Conditional deletion of SHIP-1 in hematopoietic cells in Tek-Cre/SHIP-1 mice resulted in spontaneous pulmonary inflammation with features of type 2 immune responses and airway remodeling like those seen in mice with global deletion of SHIP-1. Furthermore, when compared to wild-type control mice, Tek-Cre/SHIP-1 mice displayed a significant increase in the number of IL-5/IL-13 producing ILC2 cells in the lung at baseline and after stimulation by allergen Papain. These findings provide some hints that PI3K signaling may play a role in ILC2 cell development at baseline and in response to allergen stimulation. SHIP-1 is required for maintaining lung homeostasis potentially by restraining ILC2 cells and type 2 inflammation.

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