RESUMEN
Obesity-associated morbidity is exacerbated by abdominal obesity, which can be measured as the waist-to-hip ratio adjusted for the body mass index (WHRadjBMI). Here we identify genes associated with obesity and WHRadjBMI and characterize allele-sensitive enhancers that are predicted to regulate WHRadjBMI genes in women. We found that several waist-to-hip ratio-associated variants map within primate-specific Alu retrotransposons harboring a DNA motif associated with adipocyte differentiation. This suggests that a genetic component of adipose distribution in humans may involve co-option of retrotransposons as adipose enhancers. We evaluated the role of the strongest female WHRadjBMI-associated gene, SNX10, in adipose biology. We determined that it is required for human adipocyte differentiation and function and participates in diet-induced adipose expansion in female mice, but not males. Our data identify genes and regulatory mechanisms that underlie female-specific adipose distribution and mediate metabolic dysfunction in women.
Asunto(s)
Obesidad , Retroelementos , Humanos , Femenino , Animales , Ratones , Obesidad/genética , Obesidad/metabolismo , Adiposidad/genética , Índice de Masa Corporal , Relación Cintura-Cadera , Tejido Adiposo/metabolismo , Nexinas de Clasificación/genética , Nexinas de Clasificación/metabolismoRESUMEN
Genome-wide association studies (GWAS) have identified many disease-associated variants, yet mechanisms underlying these associations remain unclear. To understand obesity-associated variants, we generate gene regulatory annotations in adipocytes and hypothalamic neurons across cellular differentiation stages. We then test variants in 97 obesity-associated loci using a massively parallel reporter assay and identify putatively causal variants that display cell type specific or cross-tissue enhancer-modulating properties. Integrating these variants with gene regulatory information suggests genes that underlie obesity GWAS associations. We also investigate a complex genomic interval on 16p11.2 where two independent loci exhibit megabase-range, cross-locus chromatin interactions. We demonstrate that variants within these two loci regulate a shared gene set. Together, our data support a model where GWAS loci contain variants that alter enhancer activity across tissues, potentially with temporally restricted effects, to impact the expression of multiple genes. This complex model has broad implications for ongoing efforts to understand GWAS.
Asunto(s)
Adipocitos/fisiología , Elementos de Facilitación Genéticos , Pleiotropía Genética , Obesidad/genética , Adipocitos/citología , Arritmias Cardíacas/genética , Arritmias Cardíacas/patología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Estudio de Asociación del Genoma Completo , Gigantismo/genética , Gigantismo/patología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Humanos , Hipotálamo/fisiología , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , MAP Quinasa Quinasa 5/genética , Neuronas/citología , Neuronas/fisiología , Polimorfismo de Nucleótido Simple , Proteínas Quinasas/genética , Sitios de Carácter Cuantitativo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , Factores de Transcripción/genética , TranscriptomaRESUMEN
Whereas coding variants often have pleiotropic effects across multiple tissues, noncoding variants are thought to mediate their phenotypic effects by specific tissue and temporal regulation of gene expression. Here, we investigated the genetic and functional architecture of a genomic region within the FTO gene that is strongly associated with obesity risk. We show that multiple variants on a common haplotype modify the regulatory properties of several enhancers targeting IRX3 and IRX5 from megabase distances. We demonstrate that these enhancers affect gene expression in multiple tissues, including adipose and brain, and impart regulatory effects during a restricted temporal window. Our data indicate that the genetic architecture of disease-associated loci may involve extensive pleiotropy, allelic heterogeneity, shared allelic effects across tissues, and temporally restricted effects.
Asunto(s)
Tejido Adiposo/metabolismo , Encéfalo/metabolismo , Proteínas de Homeodominio/genética , Obesidad/genética , Factores de Transcripción/genética , Alelos , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Animales , Encéfalo/embriología , Línea Celular , Cromatina/química , Cromatina/metabolismo , Desarrollo Embrionario , Elementos de Facilitación Genéticos , Conducta Alimentaria , Preferencias Alimentarias , Regulación de la Expresión Génica , Haplotipos , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Obesidad/fisiopatología , Polimorfismo de Nucleótido Simple , Factores de Transcripción/metabolismoRESUMEN
There is a life-long relationship between rhinovirus (RV) infection and the development and clinical manifestations of asthma. In this study we demonstrate that cultured primary bronchial epithelial cells from adults with asthma (n = 9) show different transcriptional and chromatin responses to RV infection compared to those without asthma (n = 9). Both the number and magnitude of transcriptional and chromatin responses to RV were muted in cells from asthma cases compared to controls. Pathway analysis of the transcriptionally responsive genes revealed enrichments of apoptotic pathways in controls but inflammatory pathways in asthma cases. Using promoter capture Hi-C we tethered regions of RV-responsive chromatin to RV-responsive genes and showed enrichment of these regions and genes at asthma GWAS loci. Taken together, our studies indicate a delayed or prolonged inflammatory state in cells from asthma cases and highlight genes that may contribute to genetic risk for asthma.
Asunto(s)
Asma/metabolismo , Cromatina/metabolismo , Células Epiteliales/fisiología , Mucosa Respiratoria/citología , Rhinovirus/fisiología , Adulto , Asma/genética , Células Cultivadas , Humanos , Transcripción GenéticaRESUMEN
Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs); however, most loci are located in gene-distal non-coding regions and their target genes are not known. Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for identifying and prioritizing the functional targets of CVD associations. We validate these maps by demonstrating that promoters preferentially contact distal sequences enriched for tissue-specific transcription factor motifs and are enriched for chromatin marks that correlate with dynamic changes in gene expression. Using the CM PCHi-C map, we linked 1999 CVD-associated SNPs to 347 target genes. Remarkably, more than 90% of SNP-target gene interactions did not involve the nearest gene, while 40% of SNPs interacted with at least two genes, demonstrating the importance of considering long-range chromatin interactions when interpreting functional targets of disease loci.