TY - JOUR
T1 - MicroRNA regulation of Cbx7 mediates a switch of polycomb orthologs during ESC differentiation
AU - O'Loghlen, Ana
AU - Muñoz-Cabello, Ana M.
AU - Gaspar-Maia, Alexandre
AU - Wu, Hsan Au
AU - Banito, Ana
AU - Kunowska, Natalia
AU - Racek, Tomas
AU - Pemberton, Helen N.
AU - Beolchi, Patrizia
AU - Lavial, Fabrice
AU - Masui, Osamu
AU - Vermeulen, Michiel
AU - Carroll, Thomas
AU - Graumann, Johannes
AU - Heard, Edith
AU - Dillon, Niall
AU - Azuara, Veronique
AU - Snijders, Ambrosius P.
AU - Peters, Gordon
AU - Bernstein, Emily
AU - Gil, Jesus
N1 - Funding Information:
We thank Mathias Mann for his support; Elizabeth Duncan and David Allis for sharing the LF2 Cbx7 ESCs; and Yen-Sin Ang, Kajan Ratnakumar, Haruhiko Koseki, Adrian Bracken, Meng Li, Tristan Rodriguez, Cynthia Fisher, and Sam Wormwald for advice and reagents. This work was supported by an NYSTEM IDEA Award C024285 to E.B. E.H. and O.M. received support from the ANR and ERC Advanced Investigator award. Core support from the MRC and grants from MRC Technology, CRUK, and AICR went to fund J.G.'s research. A.M. was funded by Fundación Ramón Areces, and A.B., by the Portuguese FCT. J.G. is also supported by the EMBO Young Investigator Programme.
PY - 2012/1/6
Y1 - 2012/1/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862908896&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862908896&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2011.12.004
DO - 10.1016/j.stem.2011.12.004
M3 - Article
C2 - 22226354
AN - SCOPUS:84862908896
SN - 1934-5909
VL - 10
SP - 33
EP - 46
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 1
ER -