Great things are great in combination, like sun and sand, or peanut butter and jelly (but not peanut butter and sand). So it only seems natural to combine ChIP and bisulfite, two of the most informative epigenetic techniques. Two groups independently developed a method that successfully integrates bisulfite-seq and ChIP (Brinkman et al., 2012; Statham et al., 2012).
Both methods first perform a ChIP against a histone modification of interest, followed by adapter ligation and size selection. The library is then bisulfite treated and sequenced. These techniques differ from each other in only minor ways. Both techniques provide single-nucleotide resolution of immunoprecipitated DNA.
By performing both assays on the same sample, the confidence that a region actually carries both modifications is much stronger. Further, it can provide higher resolution than either technique performed alone. For example, Statham et al. were able to show allele-specific methylation differences in H3K27-bound regions indicating that these regions are bound by polycomb proteins independently of their methylation status. Brinkman et al. also challenge previous understanding of these modifications. They show that H3K27me3 and DNA methylation are mutually exclusive at high CpG regions.
ChIP-BS-seq & BisChIP-seq Additional Reading
Gao, F., Ji, G., Gao, Z., Han, X., Ye, M., Yuan, Z., Luo, H., Huang, X., Natarajan, K., Wang, J., Yang, H., and Zhang, X. (2014). Direct ChIP-bisulfite sequencing reveals a role of H3K27me3 mediating aberrant hypermethylation of promoter CpG islands in cancer cells. Genomics
This paper uses Chip-BS-seq to examine the role of H3K27me3 in controlling DNA methylation at CpG islands in cancer cells.
- Brinkman, A.B., Gu, H., Bartels, S.J., Zhang, Y., Matarese, F., Simmer, F., Marks, H., Bock, C., Gnirke, A., Meissner, A., and Stunnenberg, H.G. (2012). Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk. Genome Res. 22, 1128-1138.
- Statham, A.L., Robinson, M.D., Song, J.Z., Coolen, M.W., Stirzaker, C., and Clark, S.J. (2012). Bisulfite sequencing of chromatin immunoprecipitated DNA (BisChIP-seq) directly informs methylation status of histone-modified DNA. Genome Res. 22, 1120-1127.