Antibiotic-resistant infections annually claim hundreds of thousands of lives worldwide. This problem is exacerbated by exchange of resistance genes between pathogens and benign microbes from diverse ...habitats. Mapping resistance gene dissemination between humans and their environment is a public health priority. Here we characterized the bacterial community structure and resistance exchange networks of hundreds of interconnected human faecal and environmental samples from two low-income Latin American communities. We found that resistomes across habitats are generally structured by bacterial phylogeny along ecological gradients, but identified key resistance genes that cross habitat boundaries and determined their association with mobile genetic elements. We also assessed the effectiveness of widely used excreta management strategies in reducing faecal bacteria and resistance genes in these settings representative of low- and middle-income countries. Our results lay the foundation for quantitative risk assessment and surveillance of resistance gene dissemination across interconnected habitats in settings representing over two-thirds of the world's population.
Transposable elements (TEs) have deposited functional regulatory elements throughout the human genome. Although most are silenced, certain TEs have been co-opted by the host. However, a ...comprehensive, multidimensional picture of the contribution of TEs to normal human gene regulation is still lacking. Here, we quantify the epigenomic status of TEs across human anatomy and development using data from the Roadmap Epigenomics Project. We find that TEs encompass a quarter of the human regulatory epigenome, and 47% of elements can be in an active regulatory state. We demonstrate that SINEs are enriched relative to other classes for active and transcribed marks, that TEs encompass a higher proportion of enhancer states in the hematopoietic lineage, and that DNA methylation of Alu elements decreases with age, corresponding with a loss of CpG islands. Finally, we identify TEs that may perform an evolutionarily conserved regulatory function, providing a systematic profile of TE activity in normal human tissue.
Prostate cancer is the second most common cancer in men worldwide
. Over the past decade, large-scale integrative genomics efforts have enhanced our understanding of this disease by characterizing ...its genetic and epigenetic landscape in thousands of patients
. However, most tumours profiled in these studies were obtained from patients from Western populations. Here we produced and analysed whole-genome, whole-transcriptome and DNA methylation data for 208 pairs of tumour tissue samples and matched healthy control tissue from Chinese patients with primary prostate cancer. Systematic comparison with published data from 2,554 prostate tumours revealed that the genomic alteration signatures in Chinese patients were markedly distinct from those of Western cohorts: specifically, 41% of tumours contained mutations in FOXA1 and 18% each had deletions in ZNF292 and CHD1. Alterations of the genome and epigenome were correlated and were predictive of disease phenotype and progression. Coding and noncoding mutations, as well as epimutations, converged on pathways that are important for prostate cancer, providing insights into this devastating disease. These discoveries underscore the importance of including population context in constructing comprehensive genomic maps for disease.
Transposable elements (TEs) are an abundant and rich genetic resource of regulatory sequences
. Cryptic regulatory elements within TEs can be epigenetically reactivated in cancer to influence ...oncogenesis in a process termed onco-exaptation
. However, the prevalence and impact of TE onco-exaptation events across cancer types are poorly characterized. Here, we analyzed 7,769 tumors and 625 normal datasets from 15 cancer types, identifying 129 TE cryptic promoter-activation events involving 106 oncogenes across 3,864 tumors. Furthermore, we interrogated the AluJb-LIN28B candidate: the genetic deletion of the TE eliminated oncogene expression, while dynamic DNA methylation modulated promoter activity, illustrating the necessity and sufficiency of a TE for oncogene activation. Collectively, our results characterize the global profile of TE onco-exaptation and highlight this prevalent phenomenon as an important mechanism for promiscuous oncogene activation and ultimately tumorigenesis.
The microbiome of uncontacted Amerindians Clemente, Jose C; Pehrsson, Erica C; Blaser, Martin J ...
Science advances,
2015-Apr-03, Volume:
1, Issue:
3
Journal Article
Peer reviewed
Open access
Most studies of the human microbiome have focused on westernized people with life-style practices that decrease microbial survival and transmission, or on traditional societies that are currently in ...transition to westernization. We characterize the fecal, oral, and skin bacterial microbiome and resistome of members of an isolated Yanomami Amerindian village with no documented previous contact with Western people. These Yanomami harbor a microbiome with the highest diversity of bacteria and genetic functions ever reported in a human group. Despite their isolation, presumably for >11,000 years since their ancestors arrived in South America, and no known exposure to antibiotics, they harbor bacteria that carry functional antibiotic resistance (AR) genes, including those that confer resistance to synthetic antibiotics and are syntenic with mobilization elements. These results suggest that westernization significantly affects human microbiome diversity and that functional AR genes appear to be a feature of the human microbiome even in the absence of exposure to commercial antibiotics. AR genes are likely poised for mobilization and enrichment upon exposure to pharmacological levels of antibiotics. Our findings emphasize the need for extensive characterization of the function of the microbiome and resistome in remote nonwesternized populations before globalization of modern practices affects potentially beneficial bacteria harbored in the human body.
Structural variation (SV), including insertions and deletions (indels), is a primary mechanism of genome evolution. However, the mechanism by which SV contributes to epigenome evolution is poorly ...understood. In this study, we characterized the association between lineage-specific indels and epigenome differences between human and chimpanzee to investigate how SVs might have shaped the epigenetic landscape. By intersecting medium-to-large human-chimpanzee indels (20bp-50kb) with putative promoters and enhancers in cranial neural crest cells (CNCC) and repressed regions in induced pluripotent cells (iPSC), we found that ~12% indels overlap putative regulatory and repressed regions (RRRs), and 15% of these indels are associated with lineage-biased RRRs. Indel-associated putative enhancer and repressive regions are ~1.3 and ~3 times as likely to be lineage-biased, respectively, as those not associated with indels. We found a 2-fold enrichment of medium-sized indels (20bp to 50bp) in CpG island (CGI)-containing promoters than expected by chance. Lastly, from human-specific transposable element insertions, we identified putative regulatory elements, including NR2F1-bound putative CNCC enhancers derived from SVAs and putative iPSC promoters derived from LTR5s. Our results demonstrate that different types of indels are associated with specific epigenomic diversity between human and chimpanzee.
Epigenetic alterations are widespread in cancer and can complement genetic alterations to influence cancer progression and treatment outcome. To determine the potential contribution of DNAmethylation ...alterations to tumor phenotype in non-small cell lung cancer (NSCLC) in both smoker and never-smoker patients, we performed genome-wide profiling of DNA methylation in 17 primary NSCLC tumors and 10 matched normal lung samples using the complementary assays, methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylation sensitive restriction enzyme sequencing (MRE-seq). We reported recurrent methylation changes in the promoters of several genes, many previously implicated in cancer, including FAM83A and SEPT9 (hypomethylation), as well as PCDH7, NKX2-1, and SOX17 (hypermethylation). Although many methylation changes between tumors and their paired normal samples were shared across patients, several were specific to a particular smoking status. For example, never-smokers displayed a greater proportion of hypomethylated differentially methylated regions (hypoDMRs) and a greater number of recurrently hypomethylated promoters, including those of ASPSCR1, TOP2A, DPP9, and USP39, all previously linked to cancer. Changes outside of promoters were also widespread and often recurrent, particularly methylation loss over repetitive elements, highly enriched for ERV1 subfamilies. Recurrent hypoDMRs were enriched for several transcription factor binding motifs, often for genes involved in signaling and cell proliferation. For example, 71% of recurrent promoter hypoDMRs contained a motif for NKX2-1. Finally, the majority of DMRs were located within an active chromatin state in tissues profiled using the Roadmap Epigenomics data, suggesting that methylation changes may contribute to altered regulatory programs through the adaptation of cell type-specific expression programs.
We conducted a phase II study of the combination of pembrolizumab with capecitabine and oxaliplatin (CAPOX) in patients with advanced biliary tract carcinoma (BTC) to assess response rate and ...clinical efficacy. Exploratory objectives included correlative studies of immune marker expression, tumor evolution, and immune infiltration in response to treatment.
Adult patients with histologically confirmed BTC were enrolled and received oxaliplatin and pembrolizumab on day 1 of cycles 1-6. Capecitabine was administered orally twice daily as intermittent treatment, with the first dose on day 1 and the last dose on day 14 of cycles 1-6. Starting on cycle 7, pembrolizumab monotherapy was continued until disease progression. The primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, tolerability, feasibility, and response rate. Immunohistochemistry (IHC) for PD-L1 and immune infiltrates was analyzed in paired tumor biopsies, as well as bulk transcriptome and exome profiling for five patients and single-cell RNA sequencing for one partial responder.
Eleven patients enrolled, three of whom had received no prior systemic therapy. Treatment was well tolerated, and the most common treatment-related grade 3 or 4 adverse events were lymphocytopenia, anemia, and decreased platelet count. Three patients (27.3%) achieved a partial response, and six (54%) had stable disease. The disease control rate was 81.8%. The median PFS was 4.1 months with a 6-month PFS rate of 45.5%. Molecular profiling suggests qualitative differences in immune infiltration and clonal evolution based on response.
Capecitabine and oxaliplatin in combination with pembrolizumab is tolerable and a potentially effective treatment for refractory advanced BTC. This study highlights a design framework for the precise characterization of individual BTC tumors.
This study was registered in ClinicalTrials.gov (NCT03111732).
The human placenta and its specialized cytotrophoblasts rapidly develop, have a compressed lifespan, govern pregnancy outcomes, and program the offspring’s health. Understanding the molecular ...underpinnings of these behaviors informs development and disease. Profiling the extraembryonic epigenome and transcriptome during the 2nd and 3rd trimesters revealed H3K9 trimethylation overlapping deeply DNA hypomethylated domains with reduced gene expression and compartment-specific patterns that illuminated their functions. Cytotrophoblast DNA methylation increased, and several key histone modifications decreased across the genome as pregnancy advanced. Cytotrophoblasts from severe preeclampsia had substantially increased H3K27 acetylation globally and at genes that are normally downregulated at term but upregulated in this syndrome. In addition, some cases had an immature pattern of H3K27ac peaks, and others showed evidence of accelerated aging, suggesting subtype-specific alterations in severe preeclampsia. Thus, the cytotrophoblast epigenome dramatically reprograms during pregnancy, placental disease is associated with failures in this process, and H3K27 hyperacetylation is a feature of severe preeclampsia.
•The epigenome of human placental cytotrophoblasts rapidly evolves over gestation•At genome scale, DNA methylation increases, and modified histones are lost•H3K9me3 occupancy of deeply hypomethylated DNA silences cytotrophoblast genes•Global increases in H3K27ac occupancy typify placental disease, for example, severe preeclampsia
Zhang, Kim et al. show significant alterations in the cytotrophoblast epigenome over pregnancy, including increased DNA methylation and loss of modified histones. Throughout gestation, H3K9 trimethylation overlapping DNA hypomethylated domains reduces gene expression. In placental disease, for example, severe preeclampsia, cytotrophoblasts have global increases in H3K27 acetylation and at misexpressed genes.
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