Medical Science

Reading/Deciphering and Maintenance of Epigenetic Information
Jiemin Wong, The Institute of Biomedical Sciences, East China Normal University

In eukaryotic cells the genomic DNA exists in the form of chromatin. The nucleosome is the repeating unit of chromatin and is composed of an histone octamer wrapped around by 147 bp of DNA. Histone modifications and DNA modifications (methylation) are two fundamental means for regulating chromatin structure and function. It is believed that the diverse biological functions of histone modifications are at least in part mediated through the effector proteins that recognize and bind to chromatin upon the presence of a specific or a specific combination of histone modifications. Thus identification and characterization of histone modification-specific binding proteins are important for understanding the molecular mechanisms of epigenetic regulation. Using an unbiased biochemical approach, we have identified UHRF1/ICBP90 as a protein that binds specifically to histone H3 when its lysine 9 (K9) is di- or tri-methylated H3-K9. Studies from other groups indicate that UHRF1/ICBP90 also binds specifically to methylated DNA (methyl-CpG). Furthermore, UHRF1/ICBP90 is required for maintaining appropriate level of DNA methylation in mouse ES cells, presumably via its ability to target DNA methyltransferase DNMT1 to sites of DNA replication. We will discuss the mechanisms by which UHRF1/ICBP90 recognizes methylated histones and methylated DNA and the mechanisms by which it maintains DNA methylation and couples histone modifications with DNA methylation.

1. Avvakumov, G. V., Walker, J. R., Xue, S., Li, Y., Duan, S., Bronner, C., Arrowsmith, C. H., and Dhe-Paganon, S. (2008). Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature 455, 822-825.

2. Karagianni, P., Amazit, L., Qin, J., and Wong, J. (2008). ICBP90, a novel methyl K9 H3 binding protein linking protein ubiquitination with heterochromatin formation. Mol Cell Biol 28, 705-717.

3. Sharif, J., Muto, M., Takebayashi, S., Suetake, I., Iwamatsu, A., Endo, T. A., Shinga, J., Mizutani-Koseki, Y., Toyoda, T., Okamura, K., et al. (2007). The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450, 908-912.

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Medical Science

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