ABSTRACT
It had been known for decades that DNA is wound around structural units called nucleosomes in eukaryotic chromatin and that chromatin is variably compacted and remodeled during development. Higher resolution studies from the 1980s showed the existence of chromosome territories, protein-coding gene-rich and -poor regions, and fine-scale ‘topologically associated domains’ with different GC-contents and distributions of sequences derived from transposable elements. Genetic loci termed enhancers, hundreds of thousands of which exist in mammalian genomes, were found to control plant and especially animal development, apparently involving chromatin ‘looping’ to activate protein-coding genes in their vicinity. Nucleosomes were found to contain canonical and specialist histones, some specific to mammalian germ and neuronal cells. Histones were found to be subject to a bewildering variety of post-translational modifications that are imposed, interpreted and erased by protein complexes that have no intrinsic sequence specificity, including many such as Polycomb and Trithorax previously shown to be essential for the developmental regulation of gene expression. Histone modifications vary by gene expression and differentiation state. Exons are preferentially located in nucleosomes, suggesting that epigenetic control of gene expression may be exon specific. Vertebrate DNA is methylated at cytosines in CpG dinucleotides dynamically during development, perturbed in cancer, and associated with heterochromatin formation and gene repression, but little is known of the pathways that determine the locus specificity of DNA and histone modifications during development or in response to environmental parameters.
