Polycomb group proteins regulate self-renewal and differentiation in many stem cell systems. When assembled into two canonical complexes, PRC1 and PRC2, they sequentially deposit H3K27me3 and H2AK119ub histone marks and establish repressive chromatin, referred to as Polycomb domains. Non-canonical PRC1 complexes retain RING1/RNF2 E3-ubiquitin ligases but have unique sets of accessory subunits. How these non-canonical complexes recognize and regulate their gene targets remains poorly understood. Here, we show that the BCL6 co-repressor (BCOR), a member of the PRC1.1 complex, is critical for maintaining primed pluripotency in human embryonic stem cells (ESCs). BCOR depletion leads to the erosion of Polycomb domains at key developmental loci and the initiation of differentiation along endoderm and mesoderm lineages. The C terminus of BCOR regulates the assembly and targeting of the PRC1.1 complex, while the N terminus contributes to BCOR-PRC1.1 repressor function. Our findings advance understanding of Polycomb targeting and repression in ESCs and could apply broadly across developmental systems. Molecular networks responsible for the maintenance of primed pluripotency in human embryonic stem cells (hESCs) remain poorly defined. Wang et al. identify BCOR as a critical hESC regulator that defines a subtype of the PRC1.1 complexes with distinct recruitment and repression mechanisms that are essential for silencing differentiation programs in hESCs.
Bibliographical noteFunding Information:
We thank D. Huangfu (Memorial Sloan Kettering Cancer Center) the for AAVS1-TALEN vectors. Next-generation sequencing was performed by the Yale Center for Genome Analyses, the Yale Stem Cell Center Genomics Core, and the University of Minnesota Genomics Center. This work was funded by grants from the NIH ( R01GM107092 to N.B.I., R01CA071540 and R01HD084459 to V.J.B., and R01S10RR027990 to T.A.N.) and the Connecticut RMRF ( 12-SBC-YALE-10 and 16-RMB-YALE-07 to N.B.I. and 12-SCA-YALE-16 to Z.W.).
- human embryonic stem cells
- polycomb repressive complexes