Embryonic stem cell potency fluctuates with endogenous retrovirus activity.
Embryonic stem (ES) cells are derived from blastocyst-stage embryos and are thought to be functionally equivalent to the inner cell mass, which lacks the ability to produce all extraembryonic tissues. Here we identify a rare transient cell population within mouse ES and induced pluripotent stem (iPS) cell cultures that expresses high levels of transcripts found in two-cell (2C) embryos in which the blastomeres are totipotent. We genetically tagged these 2C-like ES cells and show that they lack the inner cell mass pluripotency proteins Oct4 (also known as Pou5f1), Sox2 and Nanog, and have acquired the ability to contribute to both embryonic and extraembryonic tissues. We show that nearly all ES cells cycle in and out of this privileged state, which is partially controlled by histone-modifying enzymes. Transcriptome sequencing and bioinformatic analyses showed that many 2C transcripts are initiated from long terminal repeats derived from endogenous retroviruses, suggesting this foreign sequence has helped to drive cell-fate regulation in placental mammals.
Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines, La Jolla, California 92037, USA.
Todd S
TS
Macfarlan
Wesley D
WD
Gifford
Shawn
S
Driscoll
Karen
K
Lettieri
Helen M
HM
Rowe
Dario
D
Bonanomi
Amy
A
Firth
Oded
O
Singer
Didier
D
Trono
Samuel L
SL
Pfaff
D000818:Animals; D054337:Cell Dedifferentiation / Q000235:genetics* / Q000502:physiology; D019070:Cell Lineage / Q000235:genetics; D002678:Chimera / Q000196:embryology; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism / Q000821:virology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000821:virology; D020077:Endogenous Retroviruses / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter / Q000235:genetics; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D008745:Methylation; D051379:Mice; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000821:virology; D020079:Terminal Repeat Sequences / Q000235:genetics; D039901:Totipotent Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000821:virology; D059467:Transcriptome / Q000235:genetics
D002843:Chromatin; D006657:Histones; D008239:Lysine