DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here the genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and in genomic DNA (gDNA) of paired tumor and adjacent tissues collected from a cohort of 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver or thyroid cancer and normal tissues from 90 healthy individuals. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures were identified in cfDNA that were characteristic for specific cancer types. 5hmC-based biomarkers of circulating cfDNA were highly predictive of colorectal and gastric cancers and were superior to conventional biomarkers and comparable to 5hmC biomarkers from tissue biopsies. Thus, this new strategy could lead to the development of effective, minimally invasive methods for diagnosis and prognosis of cancer from the analyses of blood samples.

ObjectiveThe lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC.DesignApplying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2554 Chinese subjects: 1204 patients with HCC, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC) and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularisation for feature selection.ResultsThe 5hmC-Seal data from patients with HCC showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer staging system from non-HCC (validation set: area under curve (AUC)=88.4%; (95% CI 85.8% to 91.1%)), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumours (eg, ≤2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC=84.6%; (95% CI 80.6% to 88.7%)), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic model appeared to be independent from potential confounders (eg, smoking/alcohol intake history).ConclusionWe have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals.

Summary We present a highly sensitive and selective chemical labeling and capture approach for genome-wide profiling of 5-hydroxylmethylcytosine (5hmC) using DNA isolated from ~1,000 cells (nano-hmC-Seal). Using this technology, we assessed 5hmC occupancy and dynamics across different stages of hematopoietic differentiation. Nano-hmC-Seal profiling of purified Tet2-mutant acute myeloid leukemia (AML) murine stem cells allowed us to identify leukemia-specific, differentially hydroxymethylated regions that harbor known and novel candidate disease-specific target genes with differential 5hmC peaks compared to normal stem cells. The change of 5hmC patterns in AML strongly correlates with differential gene expression, demonstrating the importance of dynamic alterations of 5hmC in regulating transcription in AML. Together, covalent 5hmC labeling offers an effective approach to study and detect DNA methylation dynamics in in vivo disease models and in limited clinical samples.

Idealized dynamical theories that employ a convective quasi-equilibrium (QE) treatment for the diabatic effects of moist convection have been used to explain the location, intensity, and intraseasonal evolution of monsoons. This paper examines whether observations of the earth's regional monsoons are consistent with the assumption of QE. It is shown here that in local summer climatologies based on reanalysis data, maxima of free-tropospheric temperature are, indeed, nearly collocated with maxima of subcloud equivalent potential temperature, u eb , in all monsoon regions except the North and South American monsoons. Free-tropospheric temperatures over North Africa also exhibit a strong remote influence from the South Asian monsoon. Consistent with idealized dynamical theories, peak precipitation falls slightly equatorward of the maxima in u eb and free-tropospheric temperature in regions where QE seems to hold.Vertical structures of temperature and wind reveal two types of monsoon circulations. One is the deep, moist baroclinic circulation clearly seen in the South Asian monsoon. The other is of mixed type, with the deep moist circulation superimposed on a shallow dry circulation closely associated with boundary layer temperature gradients. While the existence of a shallow dry circulation has been documented extensively in the North African monsoon, here it is shown to also exist in Australia and southern Africa during the local summer. Analogous to moist QE theories for the deep circulation, the shallow circulation can be viewed in a dry QE framework in which shallow ascent occurs just equatorward of the peak boundary layer potential temperature, u b , providing a unified system where the poleward extents of deep and shallow circulations are bounded by maxima in u eb and u b , respectively.

Protein aggregation is the hallmark of neurodegeneration but the molecular mechanisms underlying late-onset Alzheimer’s disease (AD) remain unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of post-mortem human brains to identify molecular pathways involved in AD. RNA-seq analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as main enrichments specific to AD. In turn, epigenomic profiling revealed gains of H3K27ac and H3K9ac linked to transcription, chromatin, and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, where H3K27ac and H3K9ac impact disease pathways by dysregulating transcription- and chromatin-gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.

The role of surface heat fluxes underneath cold pools is investigated using cloud‐resolving simulations with either interactive or horizontally homogenous surface heat fluxes over an ocean and a simplified land surface. Over the ocean, there are limited changes in the distribution of the cold pool temperature, humidity, and gust front velocity, yet interactive heat fluxes induce more cold pools, which are smaller, and convection is then less organized. Correspondingly, the updraft mass flux and lateral entrainment are modified. Over the land surface, the heat fluxes underneath cold pools drastically impact the cold pool characteristics with more numerous and smaller pools, which are warmer and more humid and accompanied by smaller gust front velocities. The interactive fluxes also modify the updraft mass flux and reduce convective organization. These results emphasize the importance of interactive surface fluxes instead of prescribed flux boundary conditions, as well as the formulation of surface heat fluxes, when studying convection.

SignificanceChanges in precipitation extremes under climate change are subject to substantial uncertainty. Atmospheric moisture increases alone would make extreme rain events heavier at a well-understood rate of ∼7% K−1, but a component associated with storm dynamics is much less well-understood and can either amplify or reduce that moisture-driven intensification. This paper uses an idealized modeling framework to understand the coupling of these two components, simulating one actual heavy rain event in both the present climate and hypothetical perturbed climates. The increased heating due to increased moisture drives a dynamical increase in large-scale ascent, amplifying the moisture-driven response by as much as a factor of two for warmer climates.

DNA 5-hydroxymethylcytosine (5hmC) modification is known to be associated with gene transcription and frequently used as a mark to investigate dynamic DNA methylation conversion during mammalian development and in human diseases. However, the lack of genome-wide 5hmC profiles in different human tissue types impedes drawing generalized conclusions about how 5hmC is implicated in transcription activity and tissue specificity. To meet this need, we describe the development of a 5hmC tissue map by characterizing the genomic distributions of 5hmC in 19 human tissues derived from ten organ systems. Subsequent sequencing results enabled the identification of genome-wide 5hmC distributions that uniquely separates samples by tissue type. Further comparison of the 5hmC profiles with transcriptomes and histone modifications revealed that 5hmC is preferentially enriched on tissue-specific gene bodies and enhancers. Taken together, the results provide an extensive 5hmC map across diverse human tissue types that suggests a potential role of 5hmC in tissue-specific development; as well as a resource to facilitate future studies of DNA demethylation in pathogenesis and the development of 5hmC as biomarkers.