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A validated regulatory network for Th17 cell specification.

Publication ,  Journal Article
Ciofani, M; Madar, A; Galan, C; Sellars, M; Mace, K; Pauli, F; Agarwal, A; Huang, W; Parkhurst, CN; Muratet, M; Newberry, KM; Meadows, S ...
Published in: Cell
October 12, 2012

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.

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Published In

Cell

DOI

EISSN

1097-4172

Publication Date

October 12, 2012

Volume

151

Issue

2

Start / End Page

289 / 303

Location

United States

Related Subject Headings

  • Th17 Cells
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Molecular Sequence Data
  • Mice, Knockout
  • Mice
  • Interferon Regulatory Factors
  • Humans
  • Genome-Wide Association Study
  • Gene Regulatory Networks
  • Fos-Related Antigen-2
 

Citation

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Ciofani, M., Madar, A., Galan, C., Sellars, M., Mace, K., Pauli, F., … Littman, D. R. (2012). A validated regulatory network for Th17 cell specification. Cell, 151(2), 289–303. https://doi.org/10.1016/j.cell.2012.09.016
Ciofani, Maria, Aviv Madar, Carolina Galan, Maclean Sellars, Kieran Mace, Florencia Pauli, Ashish Agarwal, et al. “A validated regulatory network for Th17 cell specification.Cell 151, no. 2 (October 12, 2012): 289–303. https://doi.org/10.1016/j.cell.2012.09.016.
Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F, et al. A validated regulatory network for Th17 cell specification. Cell. 2012 Oct 12;151(2):289–303.
Ciofani, Maria, et al. “A validated regulatory network for Th17 cell specification.Cell, vol. 151, no. 2, Oct. 2012, pp. 289–303. Pubmed, doi:10.1016/j.cell.2012.09.016.
Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F, Agarwal A, Huang W, Parkhurst CN, Muratet M, Newberry KM, Meadows S, Greenfield A, Yang Y, Jain P, Kirigin FK, Birchmeier C, Wagner EF, Murphy KM, Myers RM, Bonneau R, Littman DR. A validated regulatory network for Th17 cell specification. Cell. 2012 Oct 12;151(2):289–303.
Journal cover image

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

October 12, 2012

Volume

151

Issue

2

Start / End Page

289 / 303

Location

United States

Related Subject Headings

  • Th17 Cells
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Molecular Sequence Data
  • Mice, Knockout
  • Mice
  • Interferon Regulatory Factors
  • Humans
  • Genome-Wide Association Study
  • Gene Regulatory Networks
  • Fos-Related Antigen-2