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1.
Cell Rep ; 26(3): 788-801.e6, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30650367

RESUMO

EndoC-ßH1 is emerging as a critical human ß cell model to study the genetic and environmental etiologies of ß cell (dys)function and diabetes. Comprehensive knowledge of its molecular landscape is lacking, yet required, for effective use of this model. Here, we report chromosomal (spectral karyotyping), genetic (genotyping), epigenomic (ChIP-seq and ATAC-seq), chromatin interaction (Hi-C and Pol2 ChIA-PET), and transcriptomic (RNA-seq and miRNA-seq) maps of EndoC-ßH1. Analyses of these maps define known (e.g., PDX1 and ISL1) and putative (e.g., PCSK1 and mir-375) ß cell-specific transcriptional cis-regulatory networks and identify allelic effects on cis-regulatory element use. Importantly, comparison with maps generated in primary human islets and/or ß cells indicates preservation of chromatin looping but also highlights chromosomal aberrations and fetal genomic signatures in EndoC-ßH1. Together, these maps, and a web application we created for their exploration, provide important tools for the design of experiments to probe and manipulate the genetic programs governing ß cell identity and (dys)function in diabetes.

2.
Genetics ; 211(2): 549-562, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30593493

RESUMO

Epigenomic signatures from histone marks and transcription factor (TF)-binding sites have been used to annotate putative gene regulatory regions. However, a direct comparison of these diverse annotations is missing, and it is unclear how genetic variation within these annotations affects gene expression. Here, we compare five widely used annotations of active regulatory elements that represent high densities of one or more relevant epigenomic marks-"super" and "typical" (nonsuper) enhancers, stretch enhancers, high-occupancy target (HOT) regions, and broad domains-across the four matched human cell types for which they are available. We observe that stretch and super enhancers cover cell type-specific enhancer "chromatin states," whereas HOT regions and broad domains comprise more ubiquitous promoter states. Expression quantitative trait loci (eQTL) in stretch enhancers have significantly smaller effect sizes compared to those in HOT regions. Strikingly, chromatin accessibility QTL in stretch enhancers have significantly larger effect sizes compared to those in HOT regions. These observations suggest that stretch enhancers could harbor genetically primed chromatin to enable changes in TF binding, possibly to drive cell type-specific responses to environmental stimuli. Our results suggest that current eQTL studies are relatively underpowered or could lack the appropriate environmental context to detect genetic effects in the most cell type-specific "regulatory annotations," which likely contributes to infrequent colocalization of eQTL with genome-wide association study signals.


Assuntos
Elementos Facilitadores Genéticos , Locos de Características Quantitativas , Ativação Transcricional , Cromatina/genética , Cromatina/metabolismo , Células-Tronco Embrionárias/metabolismo , Células Hep G2 , Humanos , Especificidade de Órgãos , Fatores de Transcrição/metabolismo
3.
Hum Mol Genet ; 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30380057

RESUMO

Danforth's short tail (Sd) mice provide an excellent model for investigating the underlying etiology of human caudal birth defects, which affect 1 in 10,000 live births. Sd animals exhibit aberrant axial skeleton, urogenital, and gastrointestinal development similar to human caudal malformation syndromes including urorectal septum malformation, caudal regression, VACTERL association, and persistent cloaca. Previous studies have shown that the Sd mutation results from an endogenous retroviral (ERV) insertion upstream of the Ptf1a gene resulting in its ectopic expression at E9.5. Though the genetic lesion has been determined, the resulting epigenomic and transcriptomic changes driving the phenotype have not been investigated. Here, we performed ATAC-seq experiments on isolated E9.5 tailbud tissue, which revealed minimal changes in chromatin accessibility in Sd/Sd mutant embryos. Interestingly, chromatin changes were localized to a small interval adjacent to the Sd ERV insertion overlapping a known Ptf1a enhancer region, which is conserved in mice and humans. Furthermore, mRNA-seq experiments revealed increased transcription of PTF1A target genes and, importantly, downregulation of hedgehog pathway genes. Reduced sonic hedgehog (SHH) signaling was confirmed by in situ hybridization and immunofluorescence suggesting that the Sd phenotype results, in part, from downregulated SHH signaling. Taken together, these data demonstrate substantial transcriptome changes in the Sd mouse, and indicate that the effect of the ERV insertion on Ptf1a expression may be mediated by increased chromatin accessibility at a conserved Ptf1a enhancer. We propose that human caudal dysgenesis disorders may result from dysregulation of hedgehog signaling pathways.

4.
J Med Internet Res ; 20(9): e263, 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30249589

RESUMO

BACKGROUND: Telemonitoring of symptoms and physiological signs has been suggested as a means of early detection of chronic obstructive pulmonary disease (COPD) exacerbations, with a view to instituting timely treatment. However, algorithms to identify exacerbations result in frequent false-positive results and increased workload. Machine learning, when applied to predictive modelling, can determine patterns of risk factors useful for improving prediction quality. OBJECTIVE: Our objectives were to (1) establish whether machine learning techniques applied to telemonitoring datasets improve prediction of hospital admissions and decisions to start corticosteroids, and (2) determine whether the addition of weather data further improves such predictions. METHODS: We used daily symptoms, physiological measures, and medication data, with baseline demography, COPD severity, quality of life, and hospital admissions from a pilot and large randomized controlled trial of telemonitoring in COPD. We linked weather data from the United Kingdom meteorological service. We used feature selection and extraction techniques for time series to construct up to 153 predictive patterns (features) from symptom, medication, and physiological measurements. We used the resulting variables to construct predictive models fitted to training sets of patients and compared them with common symptom-counting algorithms. RESULTS: We had a mean 363 days of telemonitoring data from 135 patients. The two most practical traditional score-counting algorithms, restricted to cases with complete data, resulted in area under the receiver operating characteristic curve (AUC) estimates of 0.60 (95% CI 0.51-0.69) and 0.58 (95% CI 0.50-0.67) for predicting admissions based on a single day's readings. However, in a real-world scenario allowing for missing data, with greater numbers of patient daily data and hospitalizations (N=57,150, N+=55, respectively), the performance of all the traditional algorithms fell, including those based on 2 days' data. One of the most frequently used algorithms performed no better than chance. All considered machine learning models demonstrated significant improvements; the best machine learning algorithm based on 57,150 episodes resulted in an aggregated AUC of 0.74 (95% CI 0.67-0.80). Adding weather data measurements did not improve the predictive performance of the best model (AUC 0.74, 95% CI 0.69-0.79). To achieve an 80% true-positive rate (sensitivity), the traditional algorithms were associated with an 80% false-positive rate: our algorithm halved this rate to approximately 40% (specificity approximately 60%). The machine learning algorithm was moderately superior to the best symptom-counting algorithm (AUC 0.77, 95% CI 0.74-0.79 vs AUC 0.66, 95% CI 0.63-0.68) at predicting the need for corticosteroids. CONCLUSIONS: Early detection and management of COPD remains an important goal given its huge personal and economic costs. Machine learning approaches, which can be tailored to an individual's baseline profile and can learn from experience of the individual patient, are superior to existing predictive algorithms and show promise in achieving this goal. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number ISRCTN96634935; http://www.isrctn.com/ISRCTN96634935 (Archived by WebCite at http://www.webcitation.org/722YkuhAz).

5.
Pharmacogenomics J ; 18(4): 528-538, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29795407

RESUMO

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10-7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

6.
Genetics ; 206(1): 91-104, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28348060

RESUMO

We address the task of genotype imputation to a dense reference panel given genotype likelihoods computed from ultralow coverage sequencing as inputs. In this setting, the data have a high-level of missingness or uncertainty, and are thus more amenable to a probabilistic representation. Most existing imputation algorithms are not well suited for this situation, as they rely on prephasing for computational efficiency, and, without definite genotype calls, the prephasing task becomes computationally expensive. We describe GeneImp, a program for genotype imputation that does not require prephasing and is computationally tractable for whole-genome imputation. GeneImp does not explicitly model recombination, instead it capitalizes on the existence of large reference panels-comprising thousands of reference haplotypes-and assumes that the reference haplotypes can adequately represent the target haplotypes over short regions unaltered. We validate GeneImp based on data from ultralow coverage sequencing (0.5×), and compare its performance to the most recent version of BEAGLE that can perform this task. We show that GeneImp achieves imputation quality very close to that of BEAGLE, using one to two orders of magnitude less time, without an increase in memory complexity. Therefore, GeneImp is the first practical choice for whole-genome imputation to a dense reference panel when prephasing cannot be applied, for instance, in datasets produced via ultralow coverage sequencing. A related future application for GeneImp is whole-genome imputation based on the off-target reads from deep whole-exome sequencing.


Assuntos
Biologia Computacional , Genoma Humano , Genótipo , Software , Algoritmos , Frequência do Gene , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA
7.
Proc Natl Acad Sci U S A ; 114(9): 2301-2306, 2017 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-28193859

RESUMO

Genome-wide association studies (GWAS) have identified >100 independent SNPs that modulate the risk of type 2 diabetes (T2D) and related traits. However, the pathogenic mechanisms of most of these SNPs remain elusive. Here, we examined genomic, epigenomic, and transcriptomic profiles in human pancreatic islets to understand the links between genetic variation, chromatin landscape, and gene expression in the context of T2D. We first integrated genome and transcriptome variation across 112 islet samples to produce dense cis-expression quantitative trait loci (cis-eQTL) maps. Additional integration with chromatin-state maps for islets and other diverse tissue types revealed that cis-eQTLs for islet-specific genes are specifically and significantly enriched in islet stretch enhancers. High-resolution chromatin accessibility profiling using assay for transposase-accessible chromatin sequencing (ATAC-seq) in two islet samples enabled us to identify specific transcription factor (TF) footprints embedded in active regulatory elements, which are highly enriched for islet cis-eQTL. Aggregate allelic bias signatures in TF footprints enabled us de novo to reconstruct TF binding affinities genetically, which support the high-quality nature of the TF footprint predictions. Interestingly, we found that T2D GWAS loci were strikingly and specifically enriched in islet Regulatory Factor X (RFX) footprints. Remarkably, within and across independent loci, T2D risk alleles that overlap with RFX footprints uniformly disrupt the RFX motifs at high-information content positions. Together, these results suggest that common regulatory variations have shaped islet TF footprints and the transcriptome and that a confluent RFX regulatory grammar plays a significant role in the genetic component of T2D predisposition.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Genoma Humano , Ilhotas Pancreáticas/metabolismo , Locos de Características Quantitativas , Transcriptoma , Alelos , Sequência de Bases , Sítios de Ligação , Cromatina/química , Cromatina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Epigênese Genética , Perfilação da Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Impressão Genômica , Humanos , Ilhotas Pancreáticas/patologia , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Fatores de Transcrição de Fator Regulador X/genética , Fatores de Transcrição de Fator Regulador X/metabolismo
8.
Sci Rep ; 6: 28098, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27302279

RESUMO

In this study we demonstrate the potential value of Immunoglobulin G (IgG) glycosylation as a novel prognostic biomarker of colorectal cancer (CRC). We analysed plasma IgG glycans in 1229 CRC patients and correlated with survival outcomes. We assessed the predictive value of clinical algorithms and compared this to algorithms that also included glycan predictors. Decreased galactosylation, decreased sialylation (of fucosylated IgG glycan structures) and increased bisecting GlcNAc in IgG glycan structures were strongly associated with all-cause (q < 0.01) and CRC mortality (q = 0.04 for galactosylation and sialylation). Clinical algorithms showed good prediction of all-cause and CRC mortality (Harrell's C: 0.73, 0.77; AUC: 0.75, 0.79, IDI: 0.02, 0.04 respectively). The inclusion of IgG glycan data did not lead to any statistically significant improvements overall, but it improved the prediction over clinical models for stage 4 patients with the shortest follow-up time until death, with the median gain in the test AUC of 0.08. These glycan differences are consistent with significantly increased IgG pro-inflammatory activity being associated with poorer CRC prognosis, especially in late stage CRC. In the absence of validated biomarkers to improve upon prognostic information from existing clinicopathological factors, the potential of these novel IgG glycan biomarkers merits further investigation.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/patologia , Imunoglobulina G/sangue , Idoso , Algoritmos , Área Sob a Curva , Neoplasias Colorretais/sangue , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida
9.
Mol Microbiol ; 100(4): 607-20, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26815905

RESUMO

Protection against antimicrobial peptides (AMPs) often involves the parallel production of multiple, well-characterized resistance determinants. So far, little is known about how these resistance modules interact and how they jointly protect the cell. Here, we studied the interdependence between different layers of the envelope stress response of Bacillus subtilis when challenged with the lipid II cycle-inhibiting AMP bacitracin. The underlying regulatory network orchestrates the production of the ABC transporter BceAB, the UPP phosphatase BcrC and the phage-shock proteins LiaIH. Our systems-level analysis reveals a clear hierarchy, allowing us to discriminate between primary (BceAB) and secondary (BcrC and LiaIH) layers of bacitracin resistance. Deleting the primary layer provokes an enhanced induction of the secondary layer to partially compensate for this loss. This study reveals a direct role of LiaIH in bacitracin resistance, provides novel insights into the feedback regulation of the Lia system, and demonstrates a pivotal role of BcrC in maintaining cell wall homeostasis. The compensatory regulation within the bacitracin network can also explain how gene expression noise propagates between resistance layers. We suggest that this active redundancy in the bacitracin resistance network of B. subtilis is a general principle to be found in many bacterial antibiotic resistance networks.


Assuntos
Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/genética , Bacitracina/farmacologia , Proteínas de Bactérias/genética , Farmacorresistência Bacteriana , Parede Celular/metabolismo , Farmacorresistência Bacteriana/genética , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
10.
Australas Psychiatry ; 22(2): 165-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24452322

RESUMO

OBJECTIVE: The purpose of CanTeen's E-Mental Health Service for Young People Living With Cancer (YPLWC) is to meet the unique psychosocial needs of young people (12-24 years) in Australia impacted by cancer (either as a patient or family member of someone with cancer). CONCLUSIONS: This online platform will provide the primary site where all YPLWC can find information, connect with others going through a similar experience, express their feelings, utilise tools for support and access professional psychosocial support services that will meet their individual needs. The overall outcome of the service will be to ensure that the YPLWC visiting the site experience optimal psychological wellbeing. Ultimately, the service's value will be in improving the lives of young people who engage with it and the follow-on effect that this will have on their families and communities in the long-term.


Assuntos
Linhas Diretas , Internet , Serviços de Saúde Mental/organização & administração , Neoplasias/psicologia , Adolescente , Austrália , Criança , Saúde da Família , Feminino , Humanos , Masculino , Neoplasias/complicações , Adulto Jovem
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