A LIF/Nanog axis is revealed in T lymphocytes that lack MARCH-7, a RINGv E3 ligase that regulates the LIF-receptor.
Nanog is a stem cell transcription factor required for self-renewal and for maintaining pluripotency, and Nanog itself is regulated at least in part by leukaemia inhibitory factor (LIF)--a pluripotent cytokine of the IL6 family. MARCH-7 is an E-3 ligase linked to regulation of the LIF-receptor in T lymphocytes and T cells from mice that lack expression of MARCH-7 are hyper-responsive to activation signals and show a five-fold increase in LIF activity. Here we ask, does MARCH-7 influence the expression profile of Nanog during the synchronized entry of T cells into the cell cycle? We discovered that lack of MARCH-7 was permissive for Nanog expression at both transcript and protein levels during G₁/S: moreover, addition of exogenous LIF to the MARCH-7 null cells caused a further 13-fold induction of Nanog; other measured transcripts including TGFβ, p53 and STAT3 were relatively unchanged. Since lack of MARCH-7 altered responsiveness to activation signals we sought evidence for pre-existing regulatory miR's that might correlate with MARCH-7 gene dose using head-to-head comparisons between MARCH-7 null, heterozygous and wt spleen cells. 34 miRs were found including miR-346 that is known to target LIF transcripts and miR-346 is one of 16 miRs differentially expressed between hESCs and induced hiPSCs. Of the 34 miRs, 12 were known to be temporally regulated in embryonic nerve cells. In summary, in the absence of MARCH-7 a new signaling pathway is unmasked that involves Nanog expression in the T cell lineage. This is the first demonstration that T cells retain responsiveness to a LIF/Nanog axis and that this axis is linked to MARCH-7.
Department of Surgery, University of Cambridge, Cambridge, UK.
Lorraine H
LH
Thompson
Roy A
RA
Whiston
Yerzhan
Y
Rakhimov
Cristian
C
Taccioli
Chang-Gong
CG
Liu
Carlo
C
Croce
Su M
SM
Metcalfe
D000818:Animals; D002478:Cells, Cultured; D018628:Gene Dosage; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007108:Immune Tolerance / Q000235:genetics; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D008969:Molecular Sequence Data; D000071317:Nanog Homeobox Protein; D053606:Receptors, OSM-LIF / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D018398:Homeodomain Proteins; D053605:Leukemia Inhibitory Factor; D035683:MicroRNAs; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D053606:Receptors, OSM-LIF; C517825:MARCH7 protein, mouse; D044767:Ubiquitin-Protein Ligases