Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation.
In many higher organisms, 5%-15% of histone H2A is ubiquitylated at lysine 119 (uH2A). The function of this modification and the factors involved in its establishment, however, are unknown. Here we demonstrate that uH2A occurs on the inactive X chromosome in female mammals and that this correlates with recruitment of Polycomb group (PcG) proteins belonging to Polycomb repressor complex 1 (PRC1). Based on our observations, we tested the role of the PRC1 protein Ring1B and its closely related homolog Ring1A in H2A ubiquitylation. Analysis of Ring1B null embryonic stem (ES) cells revealed extensive depletion of global uH2A levels. On the inactive X chromosome, uH2A was maintained in Ring1A or Ring1B null cells, but not in double knockout cells, demonstrating an overlapping function for these proteins in development. These observations link H2A ubiquitylation, X inactivation, and PRC1 PcG function, suggesting an unanticipated and novel mechanism for chromatin-mediated heritable gene silencing.
de Napoles
Mariana
M
Developmental Epigenetics Group, MRC Clinical Sciences Centre, ICFM, Hammersmith Hospital, DuCane Road, London W12 ONN, United Kingdom.
Mermoud
Jacqueline E
JE
Wakao
Rika
R
Tang
Y Amy
YA
Endoh
Mitusuhiro
M
Appanah
Ruth
R
Nesterova
Tatyana B
TB
Silva
Jose
J
Otte
Arie P
AP
Vidal
Miguel
M
Koseki
Haruhiko
H
Brockdorff
Neil
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001755:Blastocyst / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003433:Crosses, Genetic; D004303:Dosage Compensation, Genetic; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D020868:Gene Silencing; D018390:Gene Targeting; D006657:Histones / Q000302:isolation & purification / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D015183:Restriction Mapping; D013234:Stem Cells / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C490451:Rin1 protein, mouse; D025801:Ubiquitin; D020691:rab GTP-Binding Proteins