A validated regulatory network for Th17 cell specification

·发布 2012年9月20日 ·更新 2012年11月6日

307

样本数

307

实验数

实验描述

Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively-bound BATF and IRF4 contribute to initial chromatin accessibility, and with STAT3 initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple datasets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease. 143 RNA-seq, 83 ChIP-seq, 65 ChIP-seq controls, and 16 FAIRE-seq

样本属性

application

ChIP-seq, FAIRE-seq, INPUT_RXLCh, RNA-seq

cell type

iTreg, naive CD4 T cell, Th0, Th1, Th17, Th2

control

SL1043, SL1045, SL10564, SL10566, SL10567, SL10569, SL1173, SL1234, SL1236, SL1238, SL12382, SL13364, SL13864, SL13865, SL13868, SL13869, SL13872, SL13873, SL1943, SL1947, SL2871, SL2876, SL2877, SL2999, SL3000, SL3035, SL3036, SL3038, SL3190, SL3312, SL3314, SL3319, SL3320, SL3592, SL3593, SL3778, SL3782, SL4028, SL4029, SL4425, SL6497, SL6499, SL6627, SL6630, SL6631, SL6634, SL6635, SL7826, SL7827, SL8346, SL8347, SL8356, SL8357, SL9444, SL9445, SL9446, SL9447, SL9623, SL9625, SL970, SL972, SL9856, SL9857, SL9858, SL9859

factor

B-ATF, BATF, Batf, c-Maf, CTCF, Etv6, Fosl2, H3K4me2, H3K4me3, Hif1a, IRF4, Jmjd3, Jmjd6, p300, RORg, STAT3, Stat3

genotype

24h RPMI Etv6, 24h RPMI siCntl, 24h RPMI siJmjd3, 24h RPMI siJmjd6, 24h RPMI siRorc, 24h siAes; 111011, 24h siAes; 120309b, 24h siAtf6; 111006, 24h siAtf6; 120309, 24h siBcl11b; 111011, 24h siBcl11b; 120309b, 24h siCcr6; 110930, 24h siCcr6; 111006, 24h siCcr6; 111011, 24h siCrem; 111011, 24h siCrem; 120309b, 24h siDdit3; 111011, 24h siDdit3; 120309b, 24h siEgr2; 111011, 24h siEgr2; 120309b, 24h siId2; 110930, 24h siId2; 120309, 24h siInhba; 111011, 24h siInhba; 120309b, 24h siJmjd3; 111011, 24h siJmjd3; 111029, 24h siJmjd6; 111014, 24h siJmjd6; 111029, 24h siLef1; 110930, 24h siLef1; 111029, 24h siNfatc2; 111006, 24h siNfatc2; 111029, 24h siNonTarget2; 110930, 24h siNonTarget2; 111006, 24h siNonTarget2; 111011, 24h siNonTarget2; 111014, 24h siNonTarget2; 111029, 24h siNonTarget2; 120309b, 24h siPrkrir; 111006, 24h siPrkrir; 120309, 24h siRorc; 110930, 24h siRorc; 111006, 24h siRorc; 111011, 24h siRorc; 120309, 24h siSatb1; 110930, 24h siSatb1; 120309, 24h siSirt2; 110930, 24h siSirt2; 111029, 24h siSki; 110930, 24h siSki;120309, 24h siTrib3; 110930, 24h siTrib3; 120309, 24h siZfp36l2; 111011, 24h siZfp36l2; 120309b, B-ATF ko, B-ATF ko (-/-), B-ATF wt (+/+), Batf +/+, Batf -/-, Batf ko, Batf wt, c-Maf ko, c-Maf ko (flox/CD4-Cre), c-Maf wt (+/CD4-Cre), Fosl2 +/+ CD4-Cre, Fosl2 fl/fl CD4-Cre, Hif1a +/+ CD4-Cre, Hif1a +/+ CD4-cre, Hif1a fl/fl CD4-Cre, Hif1a fl/fl CD4-cre, Ikzf3 Ikzf3 +/+, Ikzf3 Ikzf3 -/-, IRF4 +/+, IRF4 -/-, IRF4 ko, IRF4 ko (-/-), IRF4 wt, IRF4 wt (+/+), RORg ko, RORg ko (GFP KI), RORg wt, RORg wt (+/+), Stat3 +/+ CD4-Cre, Stat3 fl/fl CD4-Cre, STAT3 ko, STAT3 ko (flox/CD4-Cre), STAT3 wt (+/CD4-Cre), wt

group

1, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 2, 20, 3, 4, 5, 6, 7, 8, 9

Organism

Mus musculus

point

12h, 16h, 1h, 24h, 3h, 48h, 6h, 9h

实验信息

登记号

E-GEOD-40918

GEO 编号

GSE40918, SRP015773

实验类型

ChIP-seq, RNA-seq of coding RNA

物种

Mus musculus

发布日期

2012年9月20日

更新日期

2012年11月6日

提交者

Dan R Littman、 Carmen Birchmerier、 Carolina Galan、 Kieran Mace、 Christopher N Parkurst、 Richard M Myers、 Ashish Agarwal、 Yi Yang、 Richard Bonneau、 Francis K Kirigin、 Kenneth M Murphy、 Alex Greenfield、 Kim M Newberry、 Maria Ciofani、 Florencia Pauli、 Sarah Meadows、 Aviv Madar、 Preti Jain、 Maclean Sellars、 Erwin F Wagner、 Wendy Huang、 Michael Muratet、 Ashish Agarwal

外部链接

ArrayExpress 原始页 NCBI GEO：GSE40918, SRP015773

分析服务

A validated regulatory network for Th17 cell specification

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