Distinct Foxp3 enhancer elements coordinate development, maintenance, and function of regulatory T cells.
The transcription factor Foxp3 plays crucial roles for Treg cell development and function. Conserved non-coding sequences (CNSs) at the Foxp3 locus control Foxp3 transcription, but how they developmentally contribute to Treg cell lineage specification remains obscure. Here, we show that among Foxp3 CNSs, the promoter-upstream CNS0 and the intergenic CNS3, which bind distinct transcription factors, were activated at early stages of thymocyte differentiation prior to Foxp3 promoter activation, with sequential genomic looping bridging these regions and the promoter. While deletion of either CNS0 or CNS3 partially compromised thymic Treg cell generation, deletion of both completely abrogated the generation and impaired the stability of Foxp3 expression in residual Treg cells. As a result, CNS0 and CNS3 double-deleted mice succumbed to lethal systemic autoimmunity and inflammation. Thus, hierarchical and coordinated activation of Foxp3 CNS0 and CNS3 initiates and stabilizes Foxp3 gene expression, thereby crucially controlling Treg cell development, maintenance, and consequently immunological self-tolerance.
Pubmed ID: 33930308 RIS Download
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Antibodies used in this publication
- Histone H3K27ac (Acetyl Lys27) antibody - ChIP grade (RRID:AB_2888004)
- Streptavidin-Allophycocyanin (RRID:AB_10050396)
- Anti-Mouse IgG (whole molecule)-Peroxidase antibody produced in goat (RRID:AB_258167)
- Rabbit IgG, polyclonal Antibody (RRID:AB_2687657)
- Anti-Histone H3 (acetyl K27) antibody [EP16602] - ChIP Grade (RRID:AB_2828007)
- CTCF (RRID:AB_2753160)
- KAT3B / p300 antibody [3G230] - ChIP Grade (RRID:AB_301550)
- TET2 (D9K3E) Rabbit mAb (Mouse Specific) (RRID:AB_2800188)
- NFAT1 (D43B1) XP Rabbit mAb (RRID:AB_10834808)
- NFkappaB p65 (F-6) (RRID:AB_628017)
- c-Fos (9F6) Rabbit mAb (RRID:AB_2247211)
- STAT5a antibody [E289] (RRID:AB_778107)
- Histone H3 (tri methyl K4) antibody [mAbcam1012] - ChIP Grade (RRID:AB_442796)
- H3K4me1-human (RRID:AB_2615075)
- Rabbit Anti-Histone H3, trimethyl (Lys27) Polyclonal antibody, Unconjugated (RRID:AB_310624)
- FOXP3 Monoclonal Antibody (FJK-16s), Alexa Fluor™ 488, eBioscience (RRID:AB_763537)
- Brilliant Violet 421(TM) anti-mouse CD24 (RRID:AB_2563508)
- Brilliant Violet 421(TM) anti-mouse CD19 (RRID:AB_10895761)
- CD3e Monoclonal Antibody (145-2C11), PE, eBioscience (RRID:AB_465496)
- FITC anti-mouse CD3epsilon (RRID:AB_312671)
- CD 3e, T-cell antigen receptor complex, epsilon subunit of T3 (RRID:AB_394593)
- Alexa Fluor(R) 488 anti-mouse CD117 (c-kit) (RRID:AB_493472)
- CD2 (RRID:AB_2737708)
- Biotin anti-mouse CD4 (RRID:AB_2561504)
- CD25 Monoclonal Antibody (PC61.5), APC, eBioscience (RRID:AB_469366)
- Biotin anti-mouse CD8a (RRID:AB_312743)
- FOXP3 Monoclonal Antibody (FJK-16s), APC, eBioscience (RRID:AB_469457)
- Anti-Human/Mouse ZAP-70 PE 25 ug (RRID:AB_466140)
- PE anti-mouse TIGIT (Vstm3) (RRID:AB_10895760)
- Biotin anti-mouse TER-119/Erythroid Cells (RRID:AB_313705)
- Brilliant Violet 421(TM) anti-mouse TCR beta chain (RRID:AB_10933263)
- PE anti-mouse CD134 (OX-40) (RRID:AB_2272150)
- CD304 (Neuropilin-1) Monoclonal Antibody (3DS304M), eFluor 450, eBioscience™ (RRID:AB_2574050)
- Rat Anti-Ly-6G, Ly-6C Monoclonal Antibody, Biotin Conjugated, Clone RB6-8C5 (RRID:AB_394640)
- KLRG1 Monoclonal Antibody (2F1), PE-Cyanine7, eBioscience (RRID:AB_1518769)
- Ki-67 (RRID:AB_2266296)
- Rat Anti-IL-4 Monoclonal Antibody, Phycoerythrin Conjugated, Clone 11B11 (RRID:AB_395391)
- PE anti-mouse IL-17A (RRID:AB_315463)
- IFN gamma Monoclonal Antibody (XMG1.2), PE-Cyanine7, eBioscience (RRID:AB_469680)
- CD278 (ICOS) Monoclonal Antibody (C398.4A), APC, eBioscience (RRID:AB_11149880)
- MHC Class II (I-A/I-E) Monoclonal Antibody (M5/114.15.2), PE, eBioscience (RRID:AB_465928)
- Alexa Fluor(R) 647 anti-mouse/human Helios (RRID:AB_10660750)
- Rat Anti-Mouse GITR Monoclonal Antibody, PE-Cy7 Conjugated, Clone DTA-1 (RRID:AB_647252)
- Rat Anti-Mouse FR4 Monoclonal Antibody, APC Conjugated (RRID:AB_1645227)
- CD8α (2.43) Rat mAb (PerCP-Cy5.5® Conjugate) (RRID:AB_2799823)
- Rat Anti-CD8a Monoclonal Antibody, PerCP Conjugated, Clone 53-6.7 (RRID:AB_394573)
- CD62L (RRID:AB_10611578)
- Brilliant Violet 421(TM) anti-mouse CD45.2 (RRID:AB_2565511)
- Mouse Anti-Mouse CD45.1 Monoclonal Antibody, PerCP-Cy5.5 Conjugated, Clone A20 (RRID:AB_1727489)
- Brilliant Violet 510(TM) anti-mouse CD4 (RRID:AB_2562608)
- Purified NA/LE Hamster Anti-Mouse CD3e Clone 145-2C11 (RRID:AB_394590)
- Syrian Hamster Anti-CD28 Monoclonal Antibody, Unconjugated, Clone 37.51 (RRID:AB_394763)
- Rat Anti-CD25 Monoclonal Antibody, Phycoerythrin Conjugated, Clone PC61 (RRID:AB_395101)
- CD19 (RRID:AB_398483)
- Rat Anti-CD16 / CD32 Monoclonal Antibody, Unconjugated, Clone 2.4G2 (RRID:AB_394657)
- CD152 (CTLA-4) Monoclonal Antibody (UC10-4B9), APC, eBioscience (RRID:AB_2016700)
- CD11c (RRID:AB_395059)
- APC anti-mouse CD103 (RRID:AB_1227502)
- PE anti-mouse CD117 (c-kit) (RRID:AB_313217)
- Lineage Cocktail (RRID:AB_10053179)
- Ultra-LEAF(TM) Purified anti-mouse IL-2 (RRID:AB_11150768)
- LEAF Purified Rat IgG1, kappa isotype Ctrl (RRID:AB_326520)
- Brilliant Violet 421(TM) anti-mouse/human CD44 (RRID:AB_10895752)
- APC anti-human CD2 (RRID:AB_10895925)
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