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Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of developmental genes

Abstract

Polycomb group (PcG) proteins play important roles in repressing lineage-specific genes and maintaining the undifferentiated state of mouse embryonic stem cells (mESCs). However, how PcG proteins are recruited to their target genes is largely unknown. Here, we show that the H3K36-specific histone demethylase Kdm2b is highly expressed in mESCs and regulated by the pluripotent factors Oct4 and Sox2 directly. Depletion of Kdm2b in mESCs causes de-repression of lineage-specific genes and induces early differentiation. The function of Kdm2b depends on its CxxC-ZF domain, which mediates its genome-wide binding to CpG islands (CGIs). Kdm2b interacts with the core components of polycomb repressive complex 1 (PRC1) and recruits the complex to the CGIs of early lineage-specific genes. Thus, our study not only reveals an Oct4–Sox2–Kdm2b–PRC1–CGI regulatory axis and its function in maintaining the undifferentiated state of mESCs, but also demonstrates a critical function of Kdm2b in recruiting PRC1 to the CGIs of lineage-specific genes to repress their expression.

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Figure 1: Kdm2b is highly expressed in mESCs and is a direct target of Oct4 and Sox2.
Figure 2: Depletion of Kdm2b induces mESC differentiation and causes aberrant gene expression.
Figure 3: Knockdown of Kdm2b in mESCs induces expression of early lineage-specific differentiation genes.
Figure 4: Kdm2b binds to unmethylated CGIs in vitro and in vivo.
Figure 5: Kdm2b and PRC1 interact and co-occupy genomic loci
Figure 6: Kdm2b and Ring1b co-occupy and repress early differentiation genes.
Figure 7: Depletion of Kdm2b impairs recruitment of Ring1b to the CGIs of target genes.

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Acknowledgements

We thank R. Klose for the plasmid pGEM3z-601. This project was supported by NIH GM068804 and U01DK089565. Y.Z. is an investigator of the Howard Hughes Medical Institute.

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Authors

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J.H. and Y.Z. designed all of the experiments and wrote the manuscript. J.H. performed most of the experiments. L.S. and H.W. performed the microarray and ChIP-seq data analysis. M.W. helped in characterizing the Kdm2b complex. O.T. helped in analysing Kdm2b expression in various cells.

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Correspondence to Yi Zhang.

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He, J., Shen, L., Wan, M. et al. Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of developmental genes. Nat Cell Biol 15, 373–384 (2013). https://doi.org/10.1038/ncb2702

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