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.

As somatic cells are converted into induced pluripotent stem cells (iPSCs), their chromatin is remodeled to a pluripotent configuration with unique euchromatin-to-heterochromatin ratios, DNA methylation patterns, and enhancer and promoter status. The molecular machinery underlying this process is largely unknown. Here, we show that embryonic stem cell (ESC)-specific factors Dppa2 and Dppa4 play a key role in resetting the epigenome to a pluripotent state. They are induced in reprogramming intermediates, function as a heterodimer, and are required for efficient reprogramming of mouse and human cells. When co-expressed with Oct4, Klf4, Sox2, and Myc (OKSM) factors, Dppa2/4 yield reprogramming efficiencies that exceed 80% and accelerate reprogramming kinetics, generating iPSCs in 2 to 4 days. When bound to chromatin, Dppa2/4 initiate global chromatin decompaction via the DNA damage response pathway and contribute to downregulation of somatic genes and activation of ESC enhancers, all of which enables an efficient transition to pluripotency. Our work provides critical insights into how the epigenome is remodeled during acquisition of pluripotency.

the patients with a relatively large slope during dose reduction, almost all of them eventually relapse. By dichotomizing the patients according to their individual slopes, we find that patients with increased slopes (>0.04) have a 60.8-fold (95% CI: 14.4-548.4) increased chance for molecular relapse compared to patients with moderate slopes (Figure 1B). Summary/Conclusion: Our results demonstrate that individual patient response to TKI dose reduction (measured by BCR-ABL1/ABL1 ratio) is a promising strategy to prospectively identify a sub-cohort of patients who will almost certainly relapse after TKI cessation. Based on this information we recommend that those patients stay under continuous TKI treatment. We cannot comment on whether these patients would fare well if they remain on a de-escalated TKI dose, which we have previously shown is a valid treatment alternative (Fassoni A et al., Haematologica 2018) and associated with an improvement in side effects (Clark RE et al., Lancet Haematology 2017). Exclusion of those high-risk patients could increase the proportion of successfully stopped CML patients to about 77%.