Abstract: Histone methylation represents one of the most critical epigenetic events in DNA function
regulation in eukaryotic organisms. Classic molecular biology and genetics tools provide significant
knowledge about mechanisms and physiological roles of histone methyltransferases and demethylases
in various cellular processes. In addition to this stream line, development and application of chemistry
and chemistry-related techniques are increasingly involved in biological study, and offer information
otherwise difficult to obtain by standard molecular biology methods. Herein, we review recent
achievements and progress in developing and applying chemical and biochemical approaches in the
study of histone methylation, including chromatin immunoprecipitation, chemical ligation, mass
spectrometry, biochemical methylation and demethylation assays, and inhibitor development. These
technological advances allow histone methylation to be studied from genome-wide level to molecular
and atomic levels. With ChIP technology, information can be obtained about precise mapping of
histone methylation patterns at specific promoters, genes, or other genomic regions. MS is particularly
useful in detecting and analyzing methylation marks in histone and nonhistone protein substrates.
Chemical approaches that permit site-specific incorporation of methyl groups into histone proteins
greatly facilitate the investigation of biological impacts of methylation at individual modification sites.