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1.
Nat Commun ; 15(1): 4820, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844479

RESUMO

Chondrocyte differentiation controls skeleton development and stature. Here we provide a comprehensive map of chondrocyte-specific enhancers and show that they provide a mechanistic framework through which non-coding genetic variants can influence skeletal development and human stature. Working with fetal chondrocytes isolated from mice bearing a Col2a1 fluorescent regulatory sensor, we identify 780 genes and 2'704 putative enhancers specifically active in chondrocytes using a combination of RNA-seq, ATAC-seq and H3K27ac ChIP-seq. Most of these enhancers (74%) show pan-chondrogenic activity, with smaller populations being restricted to limb (18%) or trunk (8%) chondrocytes only. Notably, genetic variations overlapping these enhancers better explain height differences than those overlapping non-chondrogenic enhancers. Finally, targeted deletions of identified enhancers at the Fgfr3, Col2a1, Hhip and, Nkx3-2 loci confirm their role in regulating cognate genes. This enhancer map provides a framework for understanding how genes and non-coding variations influence bone development and diseases.


Assuntos
Condrócitos , Condrogênese , Elementos Facilitadores Genéticos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos , Animais , Elementos Facilitadores Genéticos/genética , Humanos , Condrócitos/metabolismo , Condrócitos/citologia , Camundongos , Condrogênese/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Desenvolvimento Ósseo/genética , Extremidades/embriologia , Masculino , Diferenciação Celular/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Feminino
2.
Clin Proteomics ; 20(1): 31, 2023 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-37550624

RESUMO

BACKGROUND: Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance. METHODS: We conducted a meta-analysis on genome-wide association studies of autosomal chromosomes in 22,997 individuals of primarily European ancestry across 12 cohorts to identify protein quantitative trait loci (pQTL) for 92 cardiometabolic associated plasma proteins. RESULTS: We identified 503 (337 cis and 166 trans) conditionally independent pQTLs, including several novel variants not reported in the literature. We conducted a sex-stratified analysis and found that 118 (23.5%) of pQTLs demonstrated heterogeneity between sexes. The direction of effect was preserved but there were differences in effect size and significance. Additionally, we annotate trans-pQTLs with nearest genes and report plausible biological relationships. Using Mendelian randomization, we identified causal associations for 18 proteins across 19 phenotypes, of which 10 have additional genetic colocalization evidence. We highlight proteins associated with a constellation of cardiometabolic traits including angiopoietin-related protein 7 (ANGPTL7) and Semaphorin 3F (SEMA3F). CONCLUSION: Through large-scale analysis of protein quantitative trait loci, we provide a comprehensive overview of common variants associated with plasma proteins. We highlight possible biological relationships which may serve as a basis for further investigation into possible causal roles in cardiometabolic diseases.

3.
Proc Natl Acad Sci U S A ; 120(17): e2205576120, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-37068238

RESUMO

Consistent evidence from human data points to successful threat-safety discrimination and responsiveness to extinction of fear memories as key characteristics of resilient individuals. To promote valid cross-species approaches for the identification of resilience mechanisms, we establish a translationally informed mouse model enabling the stratification of mice into three phenotypic subgroups following chronic social defeat stress, based on their individual ability for threat-safety discrimination and conditioned learning: the Discriminating-avoiders, characterized by successful social threat-safety discrimination and extinction of social aversive memories; the Indiscriminate-avoiders, showing aversive response generalization and resistance to extinction, in line with findings on susceptible individuals; and the Non-avoiders displaying impaired aversive conditioned learning. To explore the neurobiological mechanisms underlying the stratification, we perform transcriptome analysis within three key target regions of the fear circuitry. We identify subgroup-specific differentially expressed genes and gene networks underlying the behavioral phenotypes, i.e., the individual ability to show threat-safety discrimination and respond to extinction training. Our approach provides a translationally informed template with which to characterize the behavioral, molecular, and circuit bases of resilience in mice.


Assuntos
Condicionamento Clássico , Medo , Humanos , Camundongos , Animais , Medo/fisiologia , Condicionamento Clássico/fisiologia , Aprendizagem da Esquiva , Estresse Psicológico/genética , Afeto , Extinção Psicológica/fisiologia
4.
Commun Biol ; 6(1): 335, 2023 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-36977773

RESUMO

Studying the interplay between genetic variation, epigenetic changes, and regulation of gene expression is crucial to understand the modification of cellular states in various conditions, including immune diseases. In this study, we characterize the cell-specificity in three key cells of the human immune system by building cis maps of regulatory regions with coordinated activity (CRDs) from ChIP-seq peaks and methylation data. We find that only 33% of CRD-gene associations are shared between cell types, revealing how similarly located regulatory regions provide cell-specific modulation of gene activity. We emphasize important biological mechanisms, as most of our associations are enriched in cell-specific transcription factor binding sites, blood-traits, and immune disease-associated loci. Notably, we show that CRD-QTLs aid in interpreting GWAS findings and help prioritize variants for testing functional hypotheses within human complex diseases. Additionally, we map trans CRD regulatory associations, and among 207 trans-eQTLs discovered, 46 overlap with the QTLGen Consortium meta-analysis in whole blood, showing that mapping functional regulatory units using population genomics allows discovering important mechanisms in the regulation of gene expression in immune cells. Finally, we constitute a comprehensive resource describing multi-omics changes to gain a greater understanding of cell-type specific regulatory mechanisms of immunity.


Assuntos
Locos de Características Quantitativas , Sequências Reguladoras de Ácido Nucleico , Humanos , Sequências Reguladoras de Ácido Nucleico/genética , Epigênese Genética , Fenótipo , Variação Genética
5.
Mol Psychiatry ; 27(12): 5177-5185, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36114277

RESUMO

Schizophrenia is a polygenic psychiatric disorder with limited understanding about the mechanistic changes in gene expression regulation. To elucidate on this, we integrate interindividual variability of regulatory activity (ChIP-sequencing for H3K27ac histone mark) with gene expression and genotype data captured from the prefrontal cortex of 272 cases and controls. By measuring interindividual correlation among proximal chromatin peaks, we show that regulatory element activity is structured into 10,936 and 10,376 cis-regulatory domains in cases and controls, respectively. The schizophrenia-specific cis-regulatory domains are enriched for fetal-specific (p = 0.0014, OR = 1.52) and depleted of adult-specific regulatory activity (p = 3.04 × 10-50, OR = 0.57) and are enriched for SCZ heritability (p = 0.001). By studying the interplay among genetic variants, gene expression, and cis-regulatory domains, we ascertain that changes in coordinated regulatory activity tag alterations in gene expression levels (p = 3.43 × 10-5, OR = 1.65), unveil case-specific QTL effects, and identify regulatory machinery changes for genes affecting synaptic function and dendritic spine morphology in schizophrenia. Altogether, we show that accounting for coordinated regulatory activity provides a novel mechanistic approach to reduce the search space for unveiling genetically perturbed regulation of gene expression in schizophrenia.


Assuntos
Esquizofrenia , Adulto , Humanos , Esquizofrenia/genética , Regulação da Expressão Gênica , Córtex Pré-Frontal/metabolismo , Cromatina/metabolismo , Herança Multifatorial , Predisposição Genética para Doença
6.
Circulation ; 145(18): 1398-1411, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35387486

RESUMO

BACKGROUND: SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood. METHODS: We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data. RESULTS: We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-protein quantitative trait loci-based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10-2.42]; P=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05-2.21]; P=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08-2.37]; P=0.02). Tissue- and cell type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells. CONCLUSIONS: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Enzima de Conversão de Angiotensina 2/genética , COVID-19/genética , Estudos Transversais , Estudo de Associação Genômica Ampla , Humanos , Receptores de Coronavírus , SARS-CoV-2
7.
Nat Commun ; 12(1): 4842, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376650

RESUMO

Nearby genes are often expressed as a group. Yet, the prevalence, molecular mechanisms and genetic control of local gene co-expression are far from being understood. Here, by leveraging gene expression measurements across 49 human tissues and hundreds of individuals, we find that local gene co-expression occurs in 13% to 53% of genes per tissue. By integrating various molecular assays (e.g. ChIP-seq and Hi-C), we estimate the ability of several mechanisms, such as enhancer-gene interactions, in distinguishing gene pairs that are co-expressed from those that are not. Notably, we identify 32,636 expression quantitative trait loci (eQTLs) which associate with co-expressed gene pairs and often overlap enhancer regions. Due to affecting several genes, these eQTLs are more often associated with multiple human traits than other eQTLs. Our study paves the way to comprehend trait pleiotropy and functional interpretation of QTL and GWAS findings. All local gene co-expression identified here is available through a public database ( https://glcoex.unil.ch/ ).


Assuntos
Regulação da Expressão Gênica , Pleiotropia Genética/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Sítios de Ligação/genética , Ontologia Genética , Estudos de Associação Genética/métodos , Humanos , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/metabolismo
8.
Genome Biol ; 20(1): 227, 2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31699133

RESUMO

We present the software Condition-specific Regulatory Units Prediction (CRUP) to infer from epigenetic marks a list of regulatory units consisting of dynamically changing enhancers with their target genes. The workflow consists of a novel pre-trained enhancer predictor that can be reliably applied across cell types and species, solely based on histone modification ChIP-seq data. Enhancers are subsequently assigned to different conditions and correlated with gene expression to derive regulatory units. We thoroughly test and then apply CRUP to a rheumatoid arthritis model, identifying enhancer-gene pairs comprising known disease genes as well as new candidate genes.


Assuntos
Elementos Facilitadores Genéticos , Software , Animais , Artrite Experimental/genética , Artrite Reumatoide/genética , Sequenciamento de Cromatina por Imunoprecipitação , Código das Histonas , Camundongos
9.
Genome Med ; 10(1): 55, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-30029672

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide and is primarily treated with radiation, surgery, and platinum-based drugs like cisplatin and carboplatin. The major challenge in the treatment of NSCLC patients is intrinsic or acquired resistance to chemotherapy. Molecular markers predicting the outcome of the patients are urgently needed. METHODS: Here, we employed patient-derived xenografts (PDXs) to detect predictive methylation biomarkers for platin-based therapies. We used MeDIP-Seq to generate genome-wide DNA methylation profiles of 22 PDXs, their parental primary NSCLC, and their corresponding normal tissues and complemented the data with gene expression analyses of the same tissues. Candidate biomarkers were validated with quantitative methylation-specific PCRs (qMSP) in an independent cohort. RESULTS: Comprehensive analyses revealed that differential methylation patterns are highly similar, enriched in PDXs and lung tumor-specific when comparing differences in methylation between PDXs versus primary NSCLC. We identified a set of 40 candidate regions with methylation correlated to carboplatin response and corresponding inverse gene expression pattern even before therapy. This analysis led to the identification of a promoter CpG island methylation of LDL receptor-related protein 12 (LRP12) associated with increased resistance to carboplatin. Validation in an independent patient cohort (n = 35) confirmed that LRP12 methylation status is predictive for therapeutic response of NSCLC patients to platin therapy with a sensitivity of 80% and a specificity of 84% (p < 0.01). Similarly, we find a shorter survival time for patients with LRP12 hypermethylation in the TCGA data set for NSCLC (lung adenocarcinoma). CONCLUSIONS: Using an epigenome-wide sequencing approach, we find differential methylation patterns from primary lung cancer and PDX-derived cancers to be very similar, albeit with a lower degree of differential methylation in primary tumors. We identify LRP12 DNA methylation as a powerful predictive marker for carboplatin resistance. These findings outline a platform for the identification of epigenetic therapy resistance biomarkers based on PDX NSCLC models.


Assuntos
Biomarcadores Tumorais/genética , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA/genética , Epigenômica , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Biomarcadores Tumorais/metabolismo , Carboplatina/farmacologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Genes Supressores de Tumor , Genoma Humano , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Neoplasias Pulmonares/genética , Camundongos Nus , Regiões Promotoras Genéticas , Resultado do Tratamento
10.
Sci Rep ; 6: 30851, 2016 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-27488939

RESUMO

Since the sequencing of large genomes, many statistical features of their sequences have been found. One intriguing feature is that certain subsequences are much more abundant than others. In fact, abundances of subsequences of a given length are distributed with a scale-free power-law tail, resembling properties of human texts, such as Zipf's law. Despite recent efforts, the understanding of this phenomenon is still lacking. Here we find that selfish DNA elements, such as those belonging to the Alu family of repeats, dominate the power-law tail. Interestingly, for the Alu elements the power-law exponent increases with the length of the considered subsequences. Motivated by these observations, we develop a model of selfish DNA expansion. The predictions of this model qualitatively and quantitatively agree with the empirical observations. This allows us to estimate parameters for the process of selfish DNA spreading in a genome during its evolution. The obtained results shed light on how evolution of selfish DNA elements shapes non-trivial statistical properties of genomes.


Assuntos
Elementos Alu/genética , Evolução Molecular , Genoma Humano/genética , Modelos Genéticos , Humanos
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