title: Distinct transcriptional regulatory modules underlie STAT3's cell type-independent and cell type-specific functions.
abstract: Transcription factors (TFs) regulate gene expression by binding to short DNA sequence motifs, yet their binding specificities alone cannot explain how certain TFs drive a diversity of biological processes. In order to investigate the factors that control the functions of the pleiotropic TF STAT3, we studied its genome-wide binding patterns in four different cell types: embryonic stem cells, CD4(+) T cells, macrophages and AtT-20 cells. We describe for the first time two distinct modes of STAT3 binding. First, a small cell type-independent mode represented by a set of 35 evolutionarily conserved STAT3-binding sites that collectively regulate STAT3's own functions and cell growth. We show that STAT3 is recruited to sites with E2F1 already pre-bound before STAT3 activation. Second, a series of different transcriptional regulatory modules (TRMs) assemble around STAT3 to drive distinct transcriptional programs in the four cell types. These modules recognize cell type-specific binding sites and are associated with factors particular to each cell type. Our study illustrates the versatility of STAT3 to regulate both universal- and cell type-specific functions by means of distinct TRMs, a mechanism that might be common to other pleiotropic TFs.
authors.affiliation: World Premier International (WPI) Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, 565-0871 Osaka, Japan.
authors.forename: Andrew Paul
authors.initials: AP
authors.lastname: Hutchins
authors.forename: Diego
authors.initials: D
authors.lastname: Diez
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Shandar
authors.initials: S
authors.lastname: Ahmad
authors.forename: Ralf
authors.initials: R
authors.lastname: Jauch
authors.forename: Michel Lucien
authors.initials: ML
authors.lastname: Tremblay
authors.forename: Diego
authors.initials: D
authors.lastname: Miranda-Saavedra
mesh_terms: D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D050796:STAT3 Transcription Factor; D004247:DNA