Biology subjects

Liu, F.

Publications and source records attributed to Liu, F..

26 records · Page 2Linked to original sources

bioRxiv2017

Assessing the Gene Regulatory Landscape in 1,188 Human Tumors

Cancer is characterised by somatic genetic variation, but the effect of the majority of non-coding somatic variants and the interface with the germline genome are still unknown. We analysed the whole genome and RNA-Seq data from 1,188 human cancer patients as provided by the Pan-cancer Analysis of Whole Genomes (PCAWG) project to map cis expression quantitative trait loci of somatic and germline variation and to uncover the causes of allele-specific expression patterns in human cancers. The availability of the first large-scale dataset with both whole genome and gene expression data enabled us to uncover the effects of the non-coding variation on cancer. In addition to confirming known regulatory effects, we identified novel associations between somatic variation and expression dysregulation, in particular in distal regulatory elements. Finally, we uncovered links between somatic mutational signatures and gene expression changes, including TERT and LMO2, and we explained the inherited risk factors in APOBEC-related mutational processes. This work represents the first large-scale assessment of the effects of both germline and somatic genetic variation on gene expression in cancer and creates a valuable resource cataloguing these effects.

cancer biology↗

bioRxiv2017

PPARD regulation in gastric progenitor cells drives gastric tumorigenesis in mice

Little is known about the cell origin of gastric cancer. Peroxisome proliferator-activated receptor-delta (PPARD) is a druggable ligand-activated nuclear receptor that impacts protumorigenic cellular events. However, PPARDs role in tumorigenesis, especially gastric tumorigenesis, remains to be defined. We found that targeting PPARD overexpression in murine gastric progenitor cells (GPC), via a villin promoter, spontaneously induced gastric tumorigenesis that progressed to invasive adenocarcinoma. PPARD overexpression in GPC upregulated tumorigenic proinflammatory cytokine and CD44 expression, expanded GPC population in vivo, enhanced GPC self-renewal and proliferation in organoid cultures, and endowed these cells with tumorigenic properties. Our findings identify PPARD as a driver of gastric tumorigenesis via GPC transformation.

cancer biology↗

bioRxiv2017

Nasal and aerosol shedding of infectious influenza virus - a community based study

Little is known about the amount and infectiousness of influenza virus shed into exhaled breath. This contributes to uncertainty about the importance of airborne influenza transmission. We screened 355 symptomatic volunteers with acute respiratory illness and report 142 cases with confirmed influenza infection who provided 218 paired nasopharyngeal (NP) and 30-minute breath samples (coarse >5 m and fine <5 m fractions) on days 1 to 3 post symptom onset. We assessed viral RNA copy number for all samples and cultured NP swabs and fine aerosols. We recovered infectious virus from 52 (39%) of the fine aerosols and 150 (89%) of the NP swabs with valid cultures. The geometric mean RNA copy numbers were 3.8x104/30-min fine, 1.2x104/30-min coarse aerosol sample, and 8.2x108 per NP swab. Fine and coarse aerosol viral RNA was positively associated with body mass index (fine p<0.05, coarse p<0.10) and number of coughs (fine p<0.001, coarse p<0.01) and negatively associated with increasing days since symptom onset (fine p<0.05 to p<0.01, coarse p<0.10) in adjusted models. Fine aerosol viral RNA was also positively associated with having influenza vaccination for both the current and prior season (p<0.01). NP swab viral RNA was positively associated with upper respiratory symptoms (p<0.01) and negatively associated with age (p<0.01) but was not significantly associated with fine or coarse aerosol viral RNA or their predictors. Sneezing was rare, and sneezing and coughing were not necessary for infectious aerosol generation. Our observations suggest that influenza infection in the upper and lower airways are compartmentalized and independent.\n\nSignificanceLack of human data on influenza virus aerosol shedding fuels debate over the importance of airborne transmission. We provide overwhelming evidence that humans generate infectious aerosols and quantitative data to improve mathematical models of transmission and public health interventions. We show that sneezing is rare and not important for, and that coughing is not required for influenza virus aerosolization. Our findings, that upper and lower airway infection are independent and that fine particle exhaled aerosols reflect infection in the lung, open a new pathway for understanding the human biology of influenza infection and transmission. Our observation of an association between repeated vaccination and increased viral aerosol generation demonstrated the power of our method, but needs confirmation.

epidemiology↗

bioRxiv2017

Pan-cancer study of heterogeneous RNA aberrations

We present the most comprehensive catalogue of cancer-associated gene alterations through characterization of tumor transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes project. Using matched whole-genome sequencing data, we attributed RNA alterations to germline and somatic DNA alterations, revealing likely genetic mechanisms. We identified 444 associations of gene expression with somatic non-coding single-nucleotide variants. We found 1,872 splicing alterations associated with somatic mutation in intronic regions, including novel exonization events associated with Alu elements. Somatic copy number alterations were the major driver of total gene and allele-specific expression (ASE) variation. Additionally, 82% of gene fusions had structural variant support, including 75 of a novel class called \"bridged\" fusions, in which a third genomic location bridged two different genes. Globally, we observe transcriptomic alteration signatures that differ between cancer types and have associations with DNA mutational signatures. Given this unique dataset of RNA alterations, we also identified 1,012 genes significantly altered through both DNA and RNA mechanisms. Our study represents an extensive catalog of RNA alterations and reveals new insights into the heterogeneous molecular mechanisms of cancer gene alterations.

genomics↗

bioRxiv2017

Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, United Kingdom, and United States, comprising a total of 52,506 phenotyped individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs at a genome-wide level of significance in KITLG, DOCK8, and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level of significance. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.

genetics↗

bioRxiv2017

Variable sensitivity to DNA damaging chemotherapeutic modulated by cell type-dependent bimodal p53 dynamics

Mechanisms that determine drug sensitivity of distinct cancer types is poorly understood for most cytotoxic chemotherapy. In this study, we elucidated a new resistance mechanism to DNA damaging chemotherapeutic through modulation of p53 dynamics. While both sensitive and resistant cancer cell lines activated similar p53 oscillation followed by cell-cycle arrest in response to low dose of DNA damaging drug, they switched in a bimodal manner to monotonic or single pulse dynamics at high drug dose. Cell lines with monotonically increasing p53 underwent rapid and extensive drug-induced apoptosis, while those exhibiting a single p53 pulse mostly survived. By combining single cell imaging with computational modeling, we characterized a regulatory module involving ATM, p53, Mdm2 and Wip1, which generates bimodal p53 dynamics through coupled feed-forward and feedback, and we found that basal expression of ATM determined the differential modular output between drug sensitive and resistant lines. Moreover, we showed combinatorial inhibition of Mdm2 and Wip1 was an effective strategy to alter p53 dynamics in resistant cancer cells and sensitize their apoptotic response. Our results point to p53 pulsing as a potentially druggable mechanism that mediates resistance to cytotoxic chemotherapy.

systems biology↗

bioRxiv2017

The Rice XA21 Ectodomain Fused to the Arabidopsis EFR Cytoplasmic Domain Confers Resistance to Xanthomonas oryzae pv. oryzae

O_LIRice (Oryza sativa) plants expressing the XA21 cell surface receptor kinase are resistant to Xanthomonas oryzae pv.oryzae (Xoo) infection. We previously demonstrated that expressing a chimeric protein containing the EFR (ELONGATION FACTOR Tu RECEPTOR) ectodomain and the XA21 endodomain (EFR:XA21) in rice does not confer robust resistance to Xoo.\nC_LIO_LITo test if the XA21 ectodomain is required for Xoo resistance, we produced transgenic rice lines expressing a chimeric protein consisting of the XA21 ectodomain and EFR endodomain (XA21:EFR) and inoculated these lines with Xoo. We also tested if the XA21:EFR rice plants respond to a synthetic sulfated 21 amino acid derivative (RaxX21-sY) derived from the activator of XA21-mediated immunity, RaxX.\nC_LIO_LIWe found that five independently transformed XA21:EFR rice lines displayed resistance to Xoo as measured by lesion length analysis, and showed that five lines express markers of the XA21 defense response (generation of reactive oxygen species and defense response gene expression) after treatment with RaxX21-sY.\nC_LIO_LIOur results indicate that expression of the XA21:EFR chimeric receptor in rice confers resistance to Xoo. These results suggest that the endodomain of the EFR and XA21 immune receptors are interchangeable and the XA21 ectodomain is the key determinant conferring robust resistance to Xoo.\nC_LI

plant biology↗

bioRxiv2017

Sublethal effects of the neonicotinoid insecticide thiamethoxam on the transcriptome of the honeybee (Apis mellifera)

Neonicotinoid insecticides are now the most widely used insecticides in the world. Previous studies have indicated that sublethal doses of neonicotinoids impair learning, memory capacity, foraging and immunocompetence in honeybees (Apis mellifera). Despite this, few studies have been carried out on the molecular effects of neonicotinoids. In this study, we focus on the second-generation neonicotinoid thiamethoxam, which is currently widely used in agriculture to protect crops. Using high-throughput RNA-Seq, we investigated the transcriptome profile of honeybees after subchronic exposure to thiamethoxam (10 ppb) over 10 days. In total, 609 differentially-expressed genes (DEGs) were identified, of which 225 were up-regulated and 384 were down-regulated. The functions of some DEGs were identified, and GO enrichment analysis showed that the enriched DEGs were mainly linked to metabolism, biosynthesis and translation. KEGG pathway analysis showed that thiamethoxam affected biological processes including ribosomes, the oxidative phosphorylation pathway, tyrosine metabolism pathway, pentose and glucuronate interconversions and drug metabolism. Overall, our results provide a basis for understanding the molecular mechanisms of the complex interactions between neonicotinoid insecticides and honeybees.\n\nSummary statementNR1, Cyp6as5, nAChRa9 and nAChR{beta}2 were up-regulated in honeybees exposed to thiamethoxam, while CSP3, Obp21, defensin-1, Mrjp1, Mrjp3 and Mrjp4 were down-regulated.

molecular biology↗