Oncohistones and Gene Regulation
Today I heard a great presentation by Chao Lu from the Rockefeller University at a day-long symposium in epigenetics hosted by the New York Genome Center.
Lu’s lab uses genome-wide analysis to study oncohistones — mutations in amino acids constituting histone tails, parts of the chromatin that are subject to modifications used in turn to regulate genetic expression. They hypothesized that a mutation in the histone protein can give rise to abhorrent 3D structure of the nucleosome that houses the DNA. These mutated structures alter the micro-chemical environment surrounding the DNA, and can trap important enzymes called methyltransferases.
In a normal cell, methyltransferases function, as the name suggests, to transfer methyl residues between different sites on histone tails. The precise position of methyls on histone tails are believed to reveal a unique regulatory code — called the histone code — that regulates when and how much each human gene is expressed.
Lu’s hypothesis was confirmed by biochemical experiments in which they isolated and quantified histone modifications, both in the case of cells with oncohistones and cells with normal histones. However, genome-wide analysis they conducted showed that the positioning of histone modifications at different parts of the genome was identical in normal histone and oncohistone cases.
Therefore, oncohistones present an interesting puzzle for biology. One one hand, they seem to trap methyltransferases, responsible for maintaining the histone code. When oncohistones are present, there are large changes in the overall amounts of histone modifications in the cell nucleus. But, at the same time and remarkably, the cell is able to maintain its histone code, suggesting durability of the global map that the transcription machinery uses to express the human genome.
Overall, the key to the puzzle may lie not in the binding of the Polycomb Repressive Complex (that includes methyltransferases) to histones, but in the complementary process of RNAi. We know that histone tail modifications are also the site where the RNAi machinery engages nascent transcripts, processing the mRNA in complex ways that delete, re-arrange, and edit human genomic expression in ways critical for function and survival.
Discovered first in cancers, and therefore earning the name “oncohistones” just as “oncogenes” did decades before, oncohistones seem to be offering an opportunity to address some fundamental questions about human gene regulation.
