MicroRNA regulation of Cbx7 mediates a switch of Polycomb orthologs during ESC differentiation.
The Polycomb Group (PcG) of chromatin modifiers regulates pluripotency and differentiation. Mammalian genomes encode multiple homologs of the Polycomb repressive complex 1 (PRC1) components, including five orthologs of the Drosophila Polycomb protein (Cbx2, Cbx4, Cbx6, Cbx7, and Cbx8). We have identified Cbx7 as the primary Polycomb ortholog of PRC1 complexes in embryonic stem cells (ESCs). The expression of Cbx7 is downregulated during ESC differentiation, preceding the upregulation of Cbx2, Cbx4, and Cbx8, which are directly repressed by Cbx7. Ectopic expression of Cbx7 inhibits differentiation and X chromosome inactivation and enhances ESC self-renewal. Conversely, Cbx7 knockdown induces differentiation and derepresses lineage-specific markers. In a functional screen, we identified the miR-125 and miR-181 families as regulators of Cbx7 that are induced during ESC differentiation. Ectopic expression of these miRNAs accelerates ESC differentiation via regulation of Cbx7. These observations establish a critical role for Cbx7 and its regulatory miRNAs in determining pluripotency.
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Ana
A
O'Loghlen
Ana M
AM
Muñoz-Cabello
Alexandre
A
Gaspar-Maia
Hsan-Au
HA
Wu
Ana
A
Banito
Natalia
N
Kunowska
Tomas
T
Racek
Helen N
HN
Pemberton
Patrizia
P
Beolchi
Fabrice
F
Lavial
Osamu
O
Masui
Michiel
M
Vermeulen
Thomas
T
Carroll
Johannes
J
Graumann
Edith
E
Heard
Niall
N
Dillon
Veronique
V
Azuara
Ambrosius P
AP
Snijders
Gordon
G
Peters
Emily
E
Bernstein
Jesus
J
Gil
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D041321:Chromosomes, Human, X / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008025:Ligases; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D049951:X Chromosome Inactivation / Q000502:physiology
D000943:Antigens, Differentiation; C503627:CBX7 protein, human; C570428:CBX8 protein, human; C570426:Cbx2 protein, mouse; C519505:Cbx7 protein, mouse; D035683:MicroRNAs; D033681:Mitochondrial Membrane Transport Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; C570429:Cbx8 protein, mouse; D063150:Polycomb Repressive Complex 1; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; C570427:CBX4 protein, human