Biology subjects

Chesi, A.

Publications and source records attributed to Chesi, A..

3 recordsLinked to original sources

bioRxiv2018

Genetic And Epigenetic Fine Mapping Of Complex Trait Associated Loci In The Human Liver

Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory regions of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the impacts of genetic variation that direct histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 77 GWAS loci that have been associated with at least one complex phenotype. Our results contribute to the repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.

genetics↗

bioRxiv2018

Genome-scale Capture C promoter interaction analysis implicates novel effector genes at GWAS loci for bone mineral density

ASBTRACTOsteoporosis is a devastating disease with an essential genetic component. Genome wide association studies (GWAS) have discovered genetic variants robustly associated with bone mineral density (BMD), however they only report genomic signals and not necessarily the precise localization of culprit effector genes. Therefore, we sought to carry out physical and direct variant to gene mapping in a relevant primary human cell type. We developed SPATIaL-seq (genome-Scale, Promoter-focused Analysis of chromaTIn Looping), a massively parallel, high resolution Capture-C based method to simultaneously characterize the genome-wide interactions of all human promoters. By intersecting our SPATIaL-seq and ATAC-seq data from human mesenchymal progenitor cell -derived osteoblasts, we observed consistent contacts between candidate causal variants and putative target gene promoters in open chromatin for ~30% of the 110 BMD loci investigated. Knockdown of two novel implicated genes, ING3 at CPED1-WNT16 and EPDR1 at STARD3NL, had pronounced inhibitory effects on osteoblastogenesis. Our approach therefore aids target discovery in osteoporosis and can be applied to other common genetic diseases.

genomics↗

bioRxiv2017

A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression

Neurodegenerative diseases pose an extraordinary threat to the worlds aging population, yet no disease-modifying therapies are available. While genome-wide association studies (GWAS) have identified hundreds of novel risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Indeed, of the many thousands of SNP-trait associations identified by GWAS over the past ~10 years, very few are understood mechanistically. Here, we investigate the association of common genetic variants at the 7p21 locus with risk for the neurodegenerative disease frontotemporal lobar degeneration. We show that variants associated with disease risk correlate with increased brain expression of the 7p21 gene TMEM106B, and no other genes. Furthermore, incremental increases in TMEM106B levels result in incremental increases in lysosomal phenotypes and cell toxicity. We then combine fine-mapping, bioinformatics, and bench-based approaches to functionally characterize all candidate causal variants at this locus. This approach identified a noncoding variant, rs1990620, which differentially recruits CTCF, influencing CTCF-mediated long-range chromatin looping interactions between multiple cis-regulatory elements, including the TMEM106B promoter. Our findings thus provide an in-depth analysis of the 7p21 locus linked by GWAS to frontotemporal lobar degeneration, nominating a causal variant and a causal mechanism for allele-specific expression and disease association at this locus. Finally, we show that genetic variants associated with risk for neurodegenerative diseases beyond frontotemporal lobar degeneration are enriched in brain CTCF-binding sites genome-wide, implicating CTCF-mediated gene regulation in risk for neurodegeneration more generally.

genetics↗