Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins.

Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations. Genome sequencing efforts have identified numerous germline mutations, and large numbers of somatic genomic alterations, associated with a predisposition to cancer. However, it remains difficult to distinguish background, or 'passenger', cancer mutations from causal, or 'driver', mutations in these data sets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations. Here we test the hypothesis that genomic variations and tumour viruses may cause cancer through related mechanisms, by systematically examining host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways, such as Notch signalling and apoptosis, that go awry in cancer. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on a par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches increase the specificity of cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate the prioritization of cancer-causing driver genes to advance the understanding of the genetic basis of human cancer.

Identification of FAM111A as an SV40 host range restriction and adenovirus helper factor.

The small genome of polyomaviruses encodes a limited number of proteins that are highly dependent on interactions with host cell proteins for efficient viral replication. The SV40 large T antigen (LT) contains several discrete functional domains including the LXCXE or RB-binding motif, the DNA binding and helicase domains that contribute to the viral life cycle. In addition, the LT C-terminal region contains the host range and adenovirus helper functions required for lytic infection in certain restrictive cell types. To understand how LT affects the host cell to facilitate viral replication, we expressed full-length or functional domains of LT in cells, identified interacting host proteins and carried out expression profiling. LT perturbed the expression of p53 target genes and subsets of cell-cycle dependent genes regulated by the DREAM and the B-Myb-MuvB complexes. Affinity purification of LT followed by mass spectrometry revealed a specific interaction between the LT C-terminal region and FAM111A, a previously uncharacterized protein. Depletion of FAM111A recapitulated the effects of heterologous expression of the LT C-terminal region, including increased viral gene expression and lytic infection of SV40 host range mutants and adenovirus replication in restrictive cells. FAM111A functions as a host range restriction factor that is specifically targeted by SV40 LT.

Developmental effects of environmental enrichment on selective and auditory sustained attention.

Environmental enrichment (EE) has been used as a positive manipulation in different disease models. However, there is conflicting evidence reported in the literature about the effects of EE. Additionally, the time period that would be most beneficial in implementing environmental enrichment as an intervention is not clear. Our study aimed to systematically compare the prenatal, juvenile, mid-adolescence, and adulthood developmental trajectory to further the understanding of enriched environment's effects on selective and auditory sustained attention, corresponding to behavioral (conceived) and physiological-reflexive (non-conceived) measures. Rats were exposed for 21 days to enriched environment during various developmental periods and compared to age-matched controls. All groups were tested for long-term effects (at postnatal day 120 and onward) on selective and sustained attention. We found that the exposure to enriched environment during mid-adolescence has yielded the most significant and long-term pattern of effects, including selective and auditory sustained attention performance, increased foraging-like behavior and a significant decrease in corticosterone level. Similarly, the exposure to EE at juvenile period improved selective attention, increased foraging-like behavior, and reduced anxiety levels as reflected in the open field as well as in low corticosterone levels. These results specify a crucial period along the developmental trajectory for applying environmental enrichment. Mid-adolescence is suggested, in future basic and translational studies, as the sensitive time period that induces the most beneficial and long-term effects of EE on attention. The current findings suggest that the exposure to EE during mid-adolescence should be further considered and studied as behavioral alternative intervention, or as adjuvant behavioral therapy, aimed to decrease the probability to develop ADHD in post-adolescence period. This suggestion is highly relevant due to the debate regarding the pros and cons of screens usage (e.g. Facebook, online games, etc.) during early life that decreases environmental enrichment, especially, direct social interaction.