Many forms of cancer have multiple subtypes with different causes and clinical outcomes. Somatic tumor genomes provide a rich new source of data for uncovering these subtypes but have proven difficult to compare as two tumors rarely share the same mutations. Here, we introduce a method called Network Based Stratification (NBS) which integrates somatic tumor genomes with gene networks. This approach allows for stratification of cancer into informative subtypes by clustering together patients with mutations in similar network regions. We demonstrate NBS in ovarian, uterine and lung cancer cohorts from The Cancer Genome Atlas. For each tissue, NBS identifies clear subtypes that are predictive of clinical outcomes such as patient survival, response to therapy or tumor histology. We identify network regions characteristic of each subtype and show how mutation-derived subtypes can be used to train an mRNA expression signature which provides similar information in the absence of DNA sequence.

The first described feedback loop of the Arabidopsis circadian clock is based on reciprocal regulation between TIMING OF CAB EXPRESSION 1 (TOC1) and CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1)/LATE ELONGATED HYPOCOTYL (LHY). CCA1 and LHY are Myb transcription factors that bind directly to the TOC1 promoter to negatively regulate its expression. Conversely, the activity of TOC1 has remained less well characterized. Genetic data support that TOC1 is necessary for the reactivation of CCA1/LHY, but there is little description of its biochemical function. Here we show that TOC1 occupies specific genomic regions in the CCA1 and LHY promoters. Purified TOC1 binds directly to DNA through its CCT domain, which is similar to known DNA-binding domains. Chemical induction and transient overexpression of TOC1 in Arabidopsis seedlings cause repression of CCA1/LHY expression, demonstrating that TOC1 can repress direct targets, and mutation or deletion of the CCT domain prevents this repression showing that DNAbinding is necessary for TOC1 action. Furthermore, we use the Gal4/UAS system in Arabidopsis to show that TOC1 acts as a general transcriptional repressor, and that repression activity is in the pseudoreceiver domain of the protein. To identify the genes regulated by TOC1 on a genomic scale, we couple TOC1 chemical induction with microarray analysis and identify previously unexplored potential TOC1 targets and output pathways. Taken together, these results define a biochemical action for the core clock protein TOC1 and refine our perspective on how plant clocks function.ost organisms that experience day/night cycles have a circadian clock that phases cellular processes and behavior to specific times of day while also anticipating daily diurnal changes to confer a fitness advantage (1). The basic molecular architecture of most clocks consists of negative-feedback loops where positive and negative components control each other's expression to generate oscillations with an approximate 24-h period (1).At the core of the Arabidopsis clock, CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) (2) and LATE ELONGATED HY-POCOTYL (LHY) (3) are morning-expressed Myb transcription factors that directly bind the evening element (4, 5) in the promoters of evening-expressed genes and act as transcriptional repressors. CCA1 and LHY have redundant functions (6, 7), are often coexpressed, and make up the negative arm of the first described feedback loop in Arabidopsis by binding the promoter of TIMING OF CAB EXPRESSION 1 (TOC1) (4). Genetically, TOC1 is the positive component of this feedback loop because CCA1/LHY morning reactivation is dependent on TOC1 (4), yet TOC1 overexpression also results in lower CCA1/LHY expression (8, 9), confusing our understanding of TOC1's role in the core clock feedback loop. TOC1 is an evening-expressed protein (10) that is part of a five-member family called the PSEUDO-RESPONSE REGULATORS (PRRs) that are expressed in succession from the morning to the night in the order PRR9, PRR7, PRR5, PRR3, and then TOC1 (11). Sequence similari...

BackgroundGlobal but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans.ResultsWe first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls.ConclusionsThis study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1186-2) contains supplementary material, which is available to authorized users.

SUMMARY HIV-infected individuals are living longer on antiretroviral therapy, but many patients display signs that in some ways resemble premature aging. To investigate and quantify the impact of chronic HIV infection on aging, we report a global analysis of the whole blood DNA methylomes of 137 HIV+ individuals under sustained therapy along with 44 matched HIV− individuals. First, we develop and validate epigenetic models of aging that are independent of blood cell composition. Using these models, we find that both chronic and recent HIV infection lead to an average aging advancement of 4.9 years, increasing expected mortality risk by 19%. In addition, sustained infection results in global deregulation of the methylome across >80,000 CpGs and specific hypomethylation of the region encoding the human leukocyte antigen locus (HLA). We find that decreased HLA methylation is predictive of lower CD4/CD8 T cell ratio, linking molecular aging, epigenetic regulation and disease progression.