Open AccessNovel STAT3 Target Genes Exert Distinct Roles in the Inhibition of Mesoderm and Endoderm Differentiation in Cooperation with Nanog
Author(s) -
Bourillot PierreYves,
Aksoy Irène,
Schreiber Valerie,
Wianny Florence,
Schulz Herbert,
Hummel Oliver,
Hubner Norbert,
Savatier Pierre
Publication year - 2009
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.110
Subject(s) - biology , homeobox protein nanog , endoderm , brachyury , leukemia inhibitory factor , mesoderm , stat3 , sox2 , microbiology and biotechnology , cellular differentiation , nanog homeobox protein , embryonic stem cell , rex1 , cancer research , induced pluripotent stem cell , genetics , signal transduction , gene
Leukemia inhibitory factor (LIF) activates the transcription factor signal transducer and activator of transcription 3 (STAT3), which results in the maintenance of mouse embryonic stem cells in the pluripotent state by inhibiting both mesodermal and endodermal differentiation. How the LIF/STAT3 pathway inhibits commitment to both mesoderm and endoderm lineages is presently unknown. Using a hormone‐dependent STAT3 and with microarray analysis, we identified 58 targets of STAT3 including 20 unknown genes. Functional analysis showed that 22 among the 23 STAT3 target genes analyzed contribute to the maintenance of the undifferentiated state, as evidenced by an increase in the frequency of differentiated colonies in a self‐renewal assay and a concomitant elevation of early differentiation markers upon knockdown. Fourteen of them, including Dact1 , Klf4 , Klf5 , Rgs16 , Smad7 , Ccrn4l , Cnnm1 , Ocln , Ier3 , Pim1 , Cyr61 , and Sgk , were also regulated by Nanog. Analysis of lineage‐specific markers showed that the STAT3 target genes fell into three distinct categories, depending on their capacity to inhibit either mesoderm or endoderm differentiation or both. The identification of genes that harness self‐renewal and are downstream targets of both STAT3 and Nanog shed light on the mechanisms underlying functional redundancy between STAT3 and Nanog in mouse embryonic stem cells. STEM CELLS 2009;27:1760–1771