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Series GSE15974 Query DataSets for GSE15974
Status Public on Nov 13, 2009
Title Heparan Sulfation Dependent FGF Signalling Maintains ES Cells Primed for Differentiation in a Heterogeneous State
Organism Mus musculus
Experiment type Expression profiling by array
Summary Embryonic stem (ES) cells continuously decide whether to maintain pluripotency or differentiate. While exogenous LIF and BMP4 perpetuate a pluripotent state, less is known about factors initiating differentiation. We show that heparan sulfate (HS) proteoglycans are critical co-receptors for signals inducing ES cell differentiation. Genetic targeting of NDST1 and 2, two enzymes required for N-sulfation of proteoglycans, blocked differentiation. This phenotype was rescued by HS presented in trans or by soluble heparin. NaClO3-, which reduces sulfation of proteoglycans, potently blocked differentiation of wild type cells. Mechanistically, N-sulfation was identified to be critical for functional autocrine FGF4 signalling. Micro array analysis identified the pluripotency maintaining transcription factors Nanog, KLF2/4/8, Tbx3 and Tcf3 to be negatively regulated, whereas markers of differentiation such as Gbx2, Dnmt3b, FGF5 and Brachyury were induced by sulfation-dependent-FGFR signalling. We show that several of these genes are heterogeneously expressed in ES cells and targeting of heparan sulfation or FGFR-signalling facilitated a homogenous Nanog/KLF4/Tbx3 positive ES cell state. This finding suggests that the recently discovered heterogeneous state of ES cells is regulated by HS-dependent FGFR signalling. Similarly, culturing blastocysts with NaClO3- eliminated GATA6 positive primitive endoderm progenitors generating a homogenous Nanog positive inner cell mass. Functionally, reduction of sulfation robustly improved de novo ES cell derivation efficiency. We conclude that N-sulfated HS is required for FGF4 signalling to maintain ES cells primed for differentiation in a heterogeneous state. Inhibiting this pathway facilitates a more naïve ground state.
 
Overall design Four groups with three biological replicates and a technical duplicate in each
 
Contributor(s) Lanner F, Sohl ML, Lee KL, Holmborn K, Yang H, Wilbertz J, Poellinger L, Rossant J, Farnebo F
Citation(s) 19937756
Submission date May 06, 2009
Last update date Jun 14, 2018
Contact name Kian Leong LEE
E-mail(s) kianleong.lee@duke-nus.edu.sg
Phone +(65) 6601 3685
Organization name National University of Singapore (NUS)
Department Duke-NUS Medical School
Lab Cancer & Stem Cell Biology Program (CSCB)
Street address #07-21, 8 College Road
City Singapore
State/province Singapore
ZIP/Postal code 169857
Country Singapore
 
Platforms (1)
GPL6885 Illumina MouseRef-8 v2.0 expression beadchip
Samples (16)
GSM400305 Wild type CCE ES cells Control rep1
GSM400306 Wild type CCE ES cells Control rep2
GSM400307 Wild type CCE ES cells Control rep3
Relations
BioProject PRJNA115557

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE15974_RAW.tar 3.1 Mb (http)(custom) TAR
GSE15974_non-normalized.txt.gz 2.7 Mb (ftp)(http) TXT
Processed data included within Sample table
Raw data are available on Series record

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