TY - JOUR
T1 - A validated regulatory network for Th17 cell specification
AU - Ciofani, Maria
AU - Madar, Aviv
AU - Galan, Carolina
AU - Sellars, MacLean
AU - MacE, Kieran
AU - Pauli, Florencia
AU - Agarwal, Ashish
AU - Huang, Wendy
AU - Parkurst, Christopher N.
AU - Muratet, Michael
AU - Newberry, Kim M.
AU - Meadows, Sarah
AU - Greenfield, Alex
AU - Yang, Yi
AU - Jain, Preti
AU - Kirigin, Francis K.
AU - Birchmeier, Carmen
AU - Wagner, Erwin F.
AU - Murphy, Kenneth M.
AU - Myers, Richard M.
AU - Bonneau, Richard
AU - Littman, Dan R.
N1 - Funding Information:
We are grateful to Andrew Sczesnak for generating TDF files and for multiple other contributions to data analysis during the course of the study. We thank R. Dalla Favera for providing IRF4 mutant mice; O. Uluckan and S. Wurm for coordinating shipping of AP-1 mutant mice; K. Ward for system administration; and K. Gunsalus and M. Dustin for helpful discussions. Support was provided by NIH grants RC1 AI087266 and RC4 AI092765 (A.A., D.R.L, R.B, and R.M.M.), PN2 EY016586 (A.G., A.M, and R.B.), and IU54CA143907-01 and EY016586-06 (A.G. and R.B.); NSF grant IOS-1126971 (R.B.); fellowships from the Leukemia and Lymphoma Society and Crohn’s and Colitis Foundation of America (M.C.), the National Arthritis Research Foundation (Y.Y.); and Irvington Institute Fellowships from the Cancer Research Institute (M.S. and W.H.).
PY - 2012/10/12
Y1 - 2012/10/12
N2 - 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 data sets 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.
AB - 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 data sets 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.
UR - http://www.scopus.com/inward/record.url?scp=84867581744&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.09.016
DO - 10.1016/j.cell.2012.09.016
M3 - Article
C2 - 23021777
AN - SCOPUS:84867581744
SN - 0092-8674
VL - 151
SP - 289
EP - 303
JO - Cell
JF - Cell
IS - 2
ER -