Title
Role of Polycomb group proteins Ring1A/B and their mediated histone ubiquitination in murine embryonic stem cells.

Mitsuhiro Endoh
Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology

Abstract:
Polycomb group (PcG) genes were originally identified in Drosophila as repressors required to maintain the silenced state of homeotic loci. PcG proteins are now known to be involved in epigenetic gene silencing by chromatin modification. We have focused on the role of Polycomb group proteins Ring1A/B, the E3 ubiquitin ligases for histone H2A, in mouse embryonic stem (ES) cells, since the mechanisms by which embryonic stem (ES) cells self-renew while maintaining the ability to differentiate into virtually all adult cell types are not well understood. Our study using Ring1A/B conditional KO ES cells revealed an essential role for Ring1A/B in repressing developmental regulators in mouse ES cells and, thereby, in maintaining ES cell identity. The genome-wide mappingof Ring1 and ubiquitinated H2Aled to identifythe central targets of Polycomb silencing that are required to maintain ESC identity. We further show that the H2Aubiquitination activity of Ring1 is dispensable for its target binding and its activity to compact chromatin at Hox loci, but is indispensable for efficient repression of target genes and thereby ESC maintenance. These data demonstrate that multiple effector mechanisms including H2A ubiquitination and chromatin compaction combine to mediate Ring1-dependent repression of genes that are crucial for the maintenance of ESC identity.Utilization of these diverse effector mechanisms might provide a means to maintain a repressive state that is robust yet highly responsive to developmental cues during ES cell self-renewal and differentiation.

References:
Endoh M, Endo TA, Endoh T, Isono K-i, Sharif J, et al. Histone H2A Mono-Ubiquitination Is a Crucial Step to Mediate PRC1-Dependent Repression of Developmental Genes to Maintain ES Cell Identity. PLoS Genet 8(7): e1002774. (2012)

Endoh M, Endo TA, Endoh T, Fujimura Y, Ohara O, Toyoda T, Otte AP, Okano M, Brockdorff N, Vidal M, Koseki H.Polycomb group proteins Ring1A/B are functionally linked to the core transcriptional regulatory circuitry to maintain ES cell identity.Development. 135(8):1513-1524. (2008)