title: Analyzing Th17 cell differentiation dynamics using a novel integrative modeling framework for time-course RNA sequencing data.
abstract: BACKGROUND
  The differentiation of naive CD 4(+) helper T (Th) cells into effector Th17 cells is steered by extracellular cytokines that activate and control the lineage specific transcriptional program. While the inducing cytokine signals and core transcription factors driving the differentiation towards Th17 lineage are well known, detailed mechanistic interactions between the key components are poorly understood.
  
  
  RESULTS
  We develop an integrative modeling framework which combines RNA sequencing data with mathematical modeling and enables us to construct a mechanistic model for the core Th17 regulatory network in a data-driven manner.
  
  
  CONCLUSIONS
  Our results show significant evidence, for instance, for inhibitory mechanisms between the transcription factors and reveal a previously unknown dependency between the dosage of the inducing cytokine TGF β and the expression of the master regulator of competing (induced) regulatory T cell lineage. Further, our experimental validation approves this dependency in Th17 polarizing conditions.
authors.affiliation: Department of Computer Science, Aalto University, Aalto, FI-00076, Finland. jukka.intosalmi@aalto.fi.
authors.forename: Jukka
authors.initials: J
authors.lastname: Intosalmi
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill HillLondon, UK. helena.ahlfors@gmail.com.|Current affiliation: Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK. helena.ahlfors@gmail.com.
authors.forename: Helena
authors.initials: H
authors.lastname: Ahlfors
authors.affiliation: Department of Computer Science, Aalto University, Aalto, FI-00076, Finland. sini.rautio@aalto.fi.
authors.forename: Sini
authors.initials: S
authors.lastname: Rautio
authors.affiliation: Department of Computer Science, Aalto University, Aalto, FI-00076, Finland. henrik.mannerstrom@aalto.fi.
authors.forename: Henrik
authors.initials: H
authors.lastname: Mannerstöm
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland. zchen@btk.fi.
authors.forename: Zhi Jane
authors.initials: ZJ
authors.lastname: Chen
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland. riitta.lahesmaa@btk.fi.
authors.forename: Riitta
authors.initials: R
authors.lastname: Lahesmaa
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill HillLondon, UK. brigitta.stockinger@crick.ac.uk.
authors.forename: Brigitta
authors.initials: B
authors.lastname: Stockinger
authors.affiliation: Department of Computer Science, Aalto University, Aalto, FI-00076, Finland. harri.lahdesmaki@aalto.fi.|Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland. harri.lahdesmaki@aalto.fi.
authors.forename: Harri
authors.initials: H
authors.lastname: Lähdesmäki
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D053263:Gene Regulatory Networks; D008957:Models, Genetic; D017423:Sequence Analysis, RNA; D058504:Th17 Cells / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D016207:Cytokines; D014157:Transcription Factors; D016212:Transforming Growth Factor beta