1 Helin Group, BRIC Research Groups, BRIC, Københavns Universitet2 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet3 BRIC Administration, BRIC, Københavns Universitet4 Core facilities, BRIC Laboratories, BRIC, Københavns Universitet5 BRIC Administration, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet6 Helin Group, BRIC Research Groups, BRIC, Københavns Universitet7 Core facilities, BRIC Laboratories, BRIC, Københavns Universitet8 BRIC Administration, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet
Polycomb repressive complex 1 (PRC1) catalyzes lysine 119 monoubiquitylation on H2A (H2AK119ub1) and regulates pluripotency in embryonic stem cells (ESCs). However, the mechanisms controlling the binding of PRC1 to genomic sites and its catalytic activity are poorly understood. Here, we show that Fbxl10 interacts with Ring1B and Nspc1, forming a noncanonical PRC1 that is required for H2AK119ub1 in mouse ESCs. Genome-wide analyses reveal that Fbxl10 preferentially binds to CpG islands and colocalizes with Ring1B on Polycomb target genes. Notably, Fbxl10 depletion causes a decrease in Ring1B binding to target genes and a major loss of H2AK119ub1. Furthermore, genetic analyses demonstrate that Fbxl10 DNA binding capability and integration into PRC1 are required for H2AK119 ubiquitylation. ESCs lacking Fbxl10, like previously characterized Polycomb mutants, cannot differentiate properly. These results demonstrate that Fbxl10 has a key role in regulating Ring1B recruitment to its target genes and H2AK119 ubiquitylation in ESCs.