A validated regulatory network for Th17 cell specification

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

doi:10.1016/j.cell.2012.09.016

A validated regulatory network for Th17 cell specification

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

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Pages (from-to)	289-303
Number of pages	15
Journal	Cell
Volume	151
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2012.09.016
State	Published - Oct 12 2012

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2012.09.016

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Ciofani, M., Madar, A., Galan, C., Sellars, M., MacE, K., Pauli, F., Agarwal, A., Huang, W., Parkurst, C. N., Muratet, M., Newberry, K. M., Meadows, S., Greenfield, A., Yang, Y., Jain, P., Kirigin, F. K., Birchmeier, C., Wagner, E. F., Murphy, K. M., ... 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, M, Madar, A, Galan, C, Sellars, M, MacE, K, Pauli, F, Agarwal, A, Huang, W, Parkurst, 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 2012, 'A validated regulatory network for Th17 cell specification', Cell, vol. 151, no. 2, pp. 289-303. https://doi.org/10.1016/j.cell.2012.09.016

@article{247b6b89472a4eec8e9381e85424cfbc,

title = "A validated regulatory network for Th17 cell specification",

abstract = "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.",

author = "Maria Ciofani and Aviv Madar and Carolina Galan and MacLean Sellars and Kieran MacE and Florencia Pauli and Ashish Agarwal and Wendy Huang and Parkurst, {Christopher N.} and Michael Muratet and Newberry, {Kim M.} and Sarah Meadows and Alex Greenfield and Yi Yang and Preti Jain and Kirigin, {Francis K.} and Carmen Birchmeier and Wagner, {Erwin F.} and Murphy, {Kenneth M.} and Myers, {Richard M.} and Richard Bonneau and Littman, {Dan R.}",

note = "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{\textquoteright}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.). ",

year = "2012",

month = oct,

day = "12",

doi = "10.1016/j.cell.2012.09.016",

language = "English (US)",

volume = "151",

pages = "289--303",

journal = "Cell",

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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.

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VL - 151

SP - 289

EP - 303

JO - Cell

JF - Cell

IS - 2

ER -

A validated regulatory network for Th17 cell specification

Abstract

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