All Publications

  • DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation. Nature communications Ren, W., Fan, H., Grimm, S. A., Kim, J. J., Li, L., Guo, Y., Petell, C. J., Tan, X., Zhang, Z., Coan, J. P., Yin, J., Kim, D. I., Gao, L., Cai, L., Khudaverdyan, N., Cetin, B., Patel, D. J., Wang, Y., Cui, Q., Strahl, B. D., Gozani, O., Miller, K. M., O'Leary, S. E., Wade, P. A., Wang, G. G., Song, J. 2021; 12 (1): 2490


    DNA methylation and trimethylated histone H4 Lysine 20 (H4K20me3) constitute two important heterochromatin-enriched marks that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two chromatin modifications crosstalk. Here, we report that DNA methyltransferase 1 (DNMT1) specifically 'recognizes' H4K20me3 via its first bromo-adjacent-homology domain (DNMT1BAH1). Engagement of DNMT1BAH1-H4K20me3 ensures heterochromatin targeting of DNMT1 and DNA methylation at LINE-1 retrotransposons, and cooperates with the previously reported readout of histone H3 tail modifications (i.e., H3K9me3 and H3 ubiquitylation) by the RFTS domain to allosterically regulate DNMT1's activity. Interplay between RFTS and BAH1 domains of DNMT1 profoundly impacts DNA methylation at both global and focal levels and genomic resistance to radiation-induced damage. Together, our study establishes a direct link between H4K20me3 and DNA methylation, providing a mechanism in which multivalent recognition of repressive histone modifications by DNMT1 ensures appropriate DNA methylation patterning and genomic stability.

    View details for DOI 10.1038/s41467-021-22665-4

    View details for PubMedID 33941775

  • Multivalent tumor suppressor adenomatous polyposis coli promotes Axin biomolecular condensate formation and efficient beta-catenin degradation. Scientific reports Li, T., Ren, J., Husmann, D., Coan, J. P., Gozani, O., Chua, K. F. 2020; 10 (1): 17425


    The tumor suppressor adenomatous polyposis coli (APC) is frequently mutated in colorectal cancers. APC and Axin are core components of a destruction complex that scaffolds GSK3beta and CK1 to earmark beta-catenin for proteosomal degradation. Disruption of APC results in pathologic stabilization of beta-catenin and oncogenesis. However, the molecular mechanism by which APC promotes beta-catenin degradation is unclear. Here, we find that the intrinsically disordered region (IDR) of APC, which contains multiple beta-catenin and Axin interacting sites, undergoes liquid-liquid phase separation(LLPS) in vitro. Expression of the APC IDR in colorectal cells promotes Axin puncta formation and beta-catenin degradation. Our results support the model that multivalent interactions between APC and Axin drives the beta-catenin destruction complex to form biomolecular condensates in cells, which concentrate key components to achieve high efficient degradation of beta-catenin.

    View details for DOI 10.1038/s41598-020-74080-2

    View details for PubMedID 33060621

  • Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation. Proceedings of the National Academy of Sciences of the United States of America Ren, W., Fan, H., Grimm, S. A., Guo, Y., Kim, J. J., Yin, J., Li, L., Petell, C. J., Tan, X., Zhang, Z., Coan, J. P., Gao, L., Cai, L., Detrick, B., Cetin, B., Cui, Q., Strahl, B. D., Gozani, O., Wang, Y., Miller, K. M., O'Leary, S. E., Wade, P. A., Patel, D. J., Wang, G. G., Song, J. 2020


    In mammals, repressive histone modifications such as trimethylation of histone H3 Lys9 (H3K9me3), frequently coexist with DNA methylation, producing a more stable and silenced chromatin state. However, it remains elusive how these epigenetic modifications crosstalk. Here, through structural and biochemical characterizations, we identified the replication foci targeting sequence (RFTS) domain of maintenance DNA methyltransferase DNMT1, a module known to bind the ubiquitylated H3 (H3Ub), as a specific reader for H3K9me3/H3Ub, with the recognition mode distinct from the typical trimethyl-lysine reader. Disruption of the interaction between RFTS and the H3K9me3Ub affects the localization of DNMT1 in stem cells and profoundly impairs the global DNA methylation and genomic stability. Together, this study reveals a previously unappreciated pathway through which H3K9me3 directly reinforces DNMT1-mediated maintenance DNA methylation.

    View details for DOI 10.1073/pnas.2009316117

    View details for PubMedID 32675241

  • Binding to medium and long chain fatty acyls is a common property of HEAT and ARM repeat modules. Scientific reports Li, T., Coan, J. P., Krajewski, K., Zhang, L., Elias, J. E., Strahl, B. D., Gozani, O., Chua, K. F. 2019; 9 (1): 14226


    Covalent post-translational modification (PTM) of proteins with acyl groups of various carbon chain-lengths regulates diverse biological processes ranging from chromatin dynamics to subcellular localization. While the YEATS domain has been found to be a prominent reader of acetylation and other short acyl modifications, whether additional acyl-lysine reader domains exist, particularly for longer carbon chains, is unclear. Here, we employed a quantitative proteomic approach using various modified peptide baits to identify reader proteins of various acyl modifications. We discovered that proteins harboring HEAT and ARM repeats bind to lysine myristoylated peptides. Recombinant HEAT and ARM repeats bind to myristoylated peptides independent of the peptide sequence or the position of the myristoyl group. Indeed, HEAT and ARM repeats bind directly to medium- and long-chain free fatty acids (MCFA and LCFA). Lipidomic experiments suggest that MCFAs and LCFAs interact with HEAT and ARM repeat proteins in mammalian cells. Finally, treatment of cells with exogenous MCFAs and inhibitors of MCFA-CoA synthases increase the transactivation activity of the ARM repeat protein beta-catenin. Taken together, our results suggest an unappreciated role for fatty acids in the regulation of proteins harboring HEAT or ARM repeats.

    View details for DOI 10.1038/s41598-019-50817-6

    View details for PubMedID 31578417