Genetic integrity is crucial to normal cell function, and mutations in genes required for DNA replication and repair underlie various forms of genetic instability and disease, including cancer. One structural feature of intact genomes is runs of homopolymeric dC/dG. Here we describe an unusual mutator phenotype in Caenorhabditis elegans characterized by deletions that start around the 3' end of polyguanine tracts and terminate at variable positions 5' from such tracts. We observed deletions throughout genomic DNA in about half of polyguanine tracts examined, especially those containing 22 or more consecutive guanine nucleotides. The mutator phenotype results from disruption of the predicted gene F33H2.1, which encodes a protein with characteristics of a DEAH helicase and which we have named dog-1 (for deletions of guanine-rich DNA). Nematodes mutated in dog-1 showed germline as well as somatic deletions in genes containing polyguanine tracts, such as vab-1. We propose that DOG-1 is required to resolve the secondary structures of guanine-rich DNA that occasionally form during lagging-strand DNA synthesis.

Little is known about the regulation of neuronal and other cell-type specific epigenomes from the brain. Here, we map the genomewide distribution of trimethylated histone H3K4 (H3K4me3), a mark associated with transcriptional regulation, in neuronal and nonneuronal nuclei collected from prefrontal cortex (PFC) of 11 individuals ranging in age from 0.5 to 69 years. Massively parallel sequencing identified 12,704 H3K4me3 enriched regions (peaks), the majority located proximal to (within 2 kb of) the transcription start site (TSS) of annotated genes. These included peaks shared by neurons in comparison with three control (lymphocyte) cell types, as well as peaks specific to individual subjects. We identified 6,213 genes that show highly enriched H3K4me3 in neurons versus control. At least 1,370 loci, including annotated genes and novel transcripts, were selectively tagged with H3K4me3 in neuronal but not in nonneuronal PFC chromatin. Our results reveal agecorrelated neuronal epigenome reorganization, including decreased H3K4me3 at approximately 600 genes (many function in developmental processes) during the first year after birth. In comparison, the epigenome of aging (>60 years) PFC neurons showed less extensive changes, including increased H3K4me3 at 100 genes. These findings demonstrate that H3K4me3 in human PFC is highly regulated in a cell type-and subject-specific manner and highlight the importance of early childhood for developmentally regulated chromatin remodeling in prefrontal neurons.D evelopmentally regulated changes in histone modifications and DNA methylation, shaping gene expression patterns and genome organization, are critical intermediates for numerous genetic and environmental factors affecting neuronal functions in healthy and diseased brains (1). For example, there is increasing evidence that epigenetic alterations in the cerebral cortex and hippocampus play an important role in the etiology of schizophrenia and other neurodevelopmental disease (2, 3). Cortical neurons permanently exit from the cell cycle during the fetal period, before the dramatic changes in functional connectivity, both on a micro-(e.g., synapse) and macroscale (e.g., network activity, cortical gray matter volumes), that extend into early childhood years and continue throughout adolescence and even beyond (4, 5). To date, however, comprehensive and genomewide maps of neuronal epigenomes, and their developmental trajectories, do not exist. This critical deficiency in epigenetic information, as it pertains to the human-and more generally animal-brain, finally can be addressed because recently it became possible to efficiently separate neuronal chromatin from other chromatin in tissue, thereby avoiding potential confounds such as the highly dynamic changes in glia cell densities during cortical ontogenesis and maturation (6). Here, we employ ChIP-Seq (7) to study the genome-wide distribution of histone H3K4 trimethylation (H3K4me3)-an epigenetic mark highly enriched at start sites of actual or potential transcription (8)-in n...

Mapping histone methylation landscapes in neurons from human, chimpanzee, and macaque brains reveals coordinated, human-specific epigenetic regulation at hundreds of regulatory sequences.