Alterations in DNA methylation (DNAm) in cancer have been known for 25 years, including hypomethylation of oncogenes and hypermethylation of tumor suppressor genes1. However, most studies of cancer methylation have assumed that functionally important DNAm will occur in promoters, and that most DNAm changes in cancer occur in CpG islands2,3. Here we show that most methylation alterations in colon cancer occur not in promoters, and also not in CpG islands but in sequences up to 2 kb distant which we term “CpG island shores.” CpG island shore methylation was strongly related to gene expression, and it was highly conserved in mouse, discriminating tissue types regardless of species of origin. There was a surprising overlap (45-65%) of the location of colon cancer-related methylation changes with those that distinguished normal tissues, with hypermethylation enriched closer to the associated CpG islands, and hypomethylation enriched further from the associated CpG island and resembling non-colon normal tissues. Thus, methylation changes in cancer are at sites that vary normally in tissue differentiation, and they are consistent with the epigenetic progenitor model of cancer4, that epigenetic alterations affecting tissue-specific differentiation are the predominant mechanism by which epigenetic changes cause cancer.

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The etiology and pathophysiology of schizophrenia remain unknown. A parallel transcriptomics, proteomics and metabolomics approach was employed on human brain tissue to explore the molecular disease signatures. Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses. This was mirrored by transcriptional and metabolite perturbations. Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls, while confounding drug effects could be ruled out. We propose that oxidative stress and the ensuing cellular adaptations are linked to the schizophrenia disease process and hope that this new disease concept may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.

Inferior temporal cortex is perhaps the highest visual processing area and much anatomical work has focused on its connections with other visual areas in temporal and occipital cortex. Here we report connections of inferior temporal cortex with regions in the frontal and parietal lobes. Inferior temporal areas TEO and TE were injected with WGA-HRP and 3H-AA, respectively, or vice versa, in 1-week-old infant and 3-4-year-old adult monkeys (Macaca mulatta). The results indicated that whereas TEO has more extensive connections with parietal areas, TE has more extensive connections with prefrontal areas. Thus, in the intraparietal sulcus, area TEO is connected with areas LIPd, LIPv, and V3A, and with the as yet undefined region between LIPv and V3A, whereas the connections of TE are predominantly with LIPd, and to a lesser extent with LIPv. In the prefrontal cortex, area TE is connected with areas 8 and 45 in the inferior limb of the anterior bank of the arcuate sulcus, with area 12 on the inferior prefrontal convexity, and with areas 11 and 13 on the orbital surface. By contrast, the connections of area TEO are limited to areas 8, 45, and 12. Furthermore, within prefrontal cortex, the projections from areas TEO and TE terminate in different layers in areas 8 and 45, such that those from TEO terminate in all layers, whereas those from TEO terminate in layers I and V/VI only. In contrast to the connections of areas TEO and TE with various medial temporal-lobe and subcortical structures, which are immature in infant monkeys (Webster et al., 1991, 1993b), the connections with parietal and prefrontal areas appear adult-like as early as 1 week of age.

In development, timing is of the utmost importance, and the timing of developmental processes often changes as organisms evolve. In human evolution, developmental retardation, or neoteny, has been proposed as a possible mechanism that contributed to the rise of many human-specific features, including an increase in brain size and the emergence of human-specific cognitive traits. We analyzed mRNA expression in the prefrontal cortex of humans, chimpanzees, and rhesus macaques to determine whether human-specific neotenic changes are present at the gene expression level. We show that the brain transcriptome is dramatically remodeled during postnatal development and that developmental changes in the human brain are indeed delayed relative to other primates. This delay is not uniform across the human transcriptome but affects a specific subset of genes that play a potential role in neural development.human evolution ͉ brain development ͉ gene expression ͉ heterochrony ͉ chimpanzee