MDR: an integrative DNA N6-methyladenine and N4-methylcytosine modification database for Rosaceae

Abstract

Eukaryotic DNA methylation has been receiving increasing attention for its crucial epigenetic regulatory function. The recently developed single-molecule real-time (SMRT) sequencing technology provides an efficient way to detect DNA N⁶-methyladenine (6mA) and N⁴-methylcytosine (4mC) modifications at a single-nucleotide resolution. The family Rosaceae contains horticultural plants with a wide range of economic importance. However, little is currently known regarding the genome-wide distribution patterns and functions of 6mA and 4mC modifications in the Rosaceae. In this study, we present an integrated DNA 6mA and 4mC modification database for the Rosaceae (MDR, http://mdr.xieslab.org). MDR, the first repository for displaying and storing DNA 6mA and 4mC methylomes from SMRT sequencing data sets for Rosaceae, includes meta and statistical information, methylation densities, Gene Ontology enrichment analyses, and genome search and browse for methylated sites in NCBI. MDR provides important information regarding DNA 6mA and 4mC methylation and may help users better understand epigenetic modifications in the family Rosaceae.

References

[1] Liang, Z. et al. DNA N(6)-adenine methylation in Arabidopsis thaliana. Dev. Cell 45, 406-416 e403 (2018).

[2] Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484-492 (2012).

[3] Law, J. A. & Jacobsen, S. E. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat. Rev. Genet. 11, 204-220 (2010).

[4] Zilberman, D., Gehring, M., Tran, R. K., Ballinger, T. & Henikoff, S. Genome-wide analysis of Arabidopsis thaliana DNA methylation uncovers an interdependence between methylation and transcription. Nat. Genet. 39, 61-69 (2007).

[5] Zhang, X. et al. Genome-wide high-resolution mapping and functional analysis of DNA methylation in arabidopsis. Cell 126, 1189-1201 (2006).

[6] Mondo, S. J. et al. Widespread adenine N6-methylation of active genes in fungi. Nat. Genet. 49, 964-968 (2017).

[7] Liang, Z. et al. The N(6)-adenine methylation in yeast genome profiled by single-molecule technology. J. Genet. Genom. 45, 223-225 (2018).

[8] Fu, Y. et al. N6-methyldeoxyadenosine marks active transcription start sites in Chlamydomonas. Cell 161, 879-892 (2015).

[9] Zhou, C. et al. Identification and analysis of adenine N(6)-methylation sites in the rice genome. Nat. Plants 4, 554-563 (2018).

[10] Zhang, Q. et al. N(6)-Methyladenine DNA Methylation in Japonica and Indica Rice Genomes and its association with gene expression, plant development and stress responses. Mol. Plant 11, 1492-1508 (2018).

[11] Zhang, G. et al. N6-methyladenine DNA modification in Drosophila. Cell 161, 893-906 (2015).

[12] Wu, T. P. et al. DNA methylation on N(6)-adenine in mammalian embryonic stem cells. Nature 532, 329-333 (2016).

[13] Liu, J. et al. Abundant DNA 6mA methylation during early embryogenesis of zebrafish and pig. Nat. Commun. 7, 13052 (2016).

[14] Xiao, C. L. et al. N(6)-methyladenine DNA modification in the human genome. Mol. Cell 71, 306-318 e307 (2018).

[15] Eid, J. et al. Real-time DNA sequencing from single polymerase molecules. Science 323, 133-138 (2009).

[16] van Dijk, E. L., Jaszczyszyn, Y., Naquin, D. & Thermes, C. The third revolution in sequencing technology. Trends Genet 34, 666-681 (2018).

[17] Flusberg, B. A. et al. Direct detection of DNA methylation during single-molecule, real-time sequencing. Nat. Methods 7, 461-465 (2010).

[18] Luo, G.-Z., Blanco, M. A., Greer, E. L., He, C. & Shi, Y. DNA N6-methyladenine: a new epigenetic mark in eukaryotes?. Nat. Rev. Mol. Cell Biol. 16, 705 (2015).

[19] Laird, P. W. Principles and challenges of genomewide DNA methylation analysis. Nat. Rev. Genet 11, 191-203 (2010).

[20] Frelon, S. et al. High-performance liquid chromatography--tandem mass spectrometry measurement of radiation-induced base damage to isolated and cellular DNA. Chem. Res. Toxicol. 13, 1002-1010 (2000).

[21] Roberts, R. J. & Macelis, D. REBASE-restriction enzymes and methylases. Nucleic Acids Res. 29, 268-269 (2001).

[22] Jung, S. et al. GDR (Genome Database for Rosaceae): integrated web resources for Rosaceae genomics and genetics research. BMC Bioinforma. 5, 130 (2004).

[23] Farinati, S., Rasori, A., Varotto, S. & Bonghi, C. Rosaceae fruit development, ripening and post-harvest: an epigenetic perspective. Front. Plant Sci. 8, 1247 (2017).

[24] Jung, S. et al. 15 years of GDR: new data and functionality in the genome database for Rosaceae. Nucleic Acids Res. 47(D1), D1137-D1145 (2018).

[25] Gu, T., Ren, S., Wang, Y., Han, Y. & Li, Y. Characterization of DNA methyltransferase and demethylase genes in Fragaria vesca. Mol. Genet. Genom. 291, 1333-1345 (2016).

[26] Cheng, J. et al. Downregulation of RdDM during strawberry fruit ripening. Genome Biol. 19, 212 (2018).

[27] Ye, P. et al. MethSMRT: an integrative database for DNA N6-methyladenine and N4-methylcytosine generated by single-molecular real-time sequencing. Nucleic Acids Res. 45, D85-D89 (2017).

[28] Sood, A. J., Viner, C. & Hoffman, M. M. DNAmod: the DNA modification database. J. Chemin. 11, 30 (2019).

[29] Edger, P. P. et al. Single-molecule sequencing and optical mapping yields an improved genome of woodland strawberry (Fragaria vesca) with chromosome-scale contiguity. Gigascience 7, 1-7 (2018).

[30] Raymond, O. et al. The Rosa genome provides new insights into the domestication of modern roses. Nat. Genet. 50, 772 (2018).

[31] Jeltsch, A., Christ, F., Fatemi, M. & Roth, M. On the substrate specificity of DNA methyltransferases. adenine-N6 DNA methyltransferases also modify cytosine residues at position N4. J. Biol. Chem. 274, 19538-19544 (1999).

[32] Jeltsch, A . The cytosine N4-methyltransferase M.PvuII also modifies adenine residues. Biol. Chem. 382, 707-710 (2001).

[33] Kodama, Y., Shumway, M. & Leinonen, R., International Nucleotide Sequence Database, C. The Sequence Read Archive: explosive growth of sequencing data. Nucleic Acids Res. 40, D54-D56 (2012).

[34] Shulaev, V. et al. The genome of woodland strawberry (Fragaria vesca). Nat. Genet. 43, 109-116 (2011).

[35] Lawrence, M. et al. Software for computing and annotating genomic ranges. PLoS Comput. Biol. 9, e1003118 (2013).

[36] Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841-842 (2010).

[37] Bailey, T. L. et al. MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 37, W202-W208 (2009).

[38] Camacho, C. et al. BLAST+: architecture and applications. BMC Bioinforma. 10, 421 (2009).