The study of chromatin biology has emerged as a new paradigm to understand the pathophysiology of critical events responsible for diseases such as cancer [1–3], diabetes [4, 5], cardiomyopathies , ageing  and many others. Chromatin is a compact, but remarkably dynamic, structure that plays a critical role in transcription, DNA replication and repair [8, 9]. Its structure and function is regulated through covalent modifications of DNA and nucleosome histones as well as substitution by a variety of histone variants.
Mammalian DNA can be modified by cytosine methylation which involves the addition of a methyl group to the 5 position of a cytosine (5mC) generally, but not always , preceding guanosine in the DNA sequence (cytosine-phosphate-guanine, CpG). Mammalian DNA methylation is mediated by DNA methyltransferases (DNMTs) including DNMT1 (responsible for maintaining proper methylation levels during replication and possibly DNA repair), DNMT3a and DNMT3b (responsible for de novo methylation during embryogenesis) . CpG islands are genomic regions that contain a high frequency of CpG sites typically > 300 base pairs in length. Most studies have focused on methylation of CpG islands in the gene's promoter region where it is associated with gene repression . This is thought to result from a blockade of transcription factor binding to genomic targets . Although methylation of CpG islands nested within transcribed regions has not been extensively studied, new evidence suggests that the role of DNA methylation in transcription elongation and termination is just as important as CpG methylation in the regulation of transcription initiation [14–16]. Because of its importance in biology of disease several different methods were developed to assay DNA methylation. Bisulfite sequencing, bisulfite conversion-based MethyLight, methylation-sensitive digestion, and methyl-DNA immunoprecipitation (MeDIP) are some of the well established methods to assay DNA methylation both at specific sites and genome-wide [10, 17–20]. Because of its simplicity and low cost MeDIP is increasingly becoming a popular method .
Histone post-translational modifications (PTMs; e.g., include acetylation, methylation, and phosphorylation) are the major avenues that regulate chromatin dynamics: they expose, or close, docking sites for a host of other molecules, including chromatin remodeling and transcription factors [9, 22, 23]. To date, more than 100 different histone amino acid residues have been shown to be modified [9, 24, 25]. A host of enzymes that modify specific histone amino acid residues have been identified [8, 9, 24]. These include, but are not limited to, histone methyltransferases , demethylases , acetyltransferases , deacetylases , kinases [29, 30] and phosphatases . Many, if not most of these enzymes, are directly recruited to specific genomic regions, for example, very recently kinases [32–36] and phosphatases [31, 36–38] were discovered to be directly recruited to their target genes. The significant progress in this area of research was facilitated by the introduction of the chromatin immunoprecipitation (ChIP) assay [39–41].
Although chromatin studies are providing compelling evidence for dynamic interchange between histones and DNA methylation , typically DNA methylation and histone modification studies have been done independently of each other and most often by different laboratories using low throughput technologies. Here, we describe a simple and easy-to-use microplate-based platform for combined analysis of DNA methylation, histone modifications and chromatin-bound enzymes, Matrix ChIP-MeDIP.