Biology subjects

Trizzino, M.

Publications and source records attributed to Trizzino, M..

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

Transposable elements generate regulatory novelty in a tissue specific fashion

BackgroundTransposable elements (TE) are an important source of evolutionary novelty in gene regulation. However, the mechanisms by which TEs contribute to gene expression are largely uncharacterized.\n\nResultsHere, we leverage Roadmap and GTEx data to investigate the association of TEs with active and repressed chromatin in 24 tissues. We find 112 human TE types enriched in active regions of the genome across tissues. SINEs and DNA transposons are the most frequently enriched classes, while LTRs are often enriched in a tissue-specific manner. We report across-tissue variability in TE enrichment in active regions. Genes with consistent expression across tissues are less likely to be associated with TE insertions. TE presence in repressed regions similarly follows tissue-specific patterns. Moreover, different TE classes correlate with different repressive marks: Long Terminal Repeat Retrotransposons (LTRs) and Long Interspersed Nuclear Elements (LINEs) are overrepresented in regions marked by H3K9me3, while the other TEs are more likely to overlap regions with H3K27me3. Young TEs are typically enriched in repressed regions and depleted in active regions. We detect multiple instances of TEs that are enriched in tissue-specific active regulatory regions. Such TEs contain binding sites for transcription factors that are master regulators for the given tissue. These TEs are enriched in intronic enhancers, and their tissue-specific enrichment correlates with tissue-specific variations in the expression of the nearest genes.\n\nConclusionsWe provide an integrated overview of the contribution of TEs to human gene regulation. Expanding previous analyses, we demonstrate that TEs can potentially contribute to the turnover of regulatory sequences in a tissue-specific fashion.

genomics↗

bioRxiv2016

Transposable element exaptation is the primary source of novelty in the primate gene regulatory landscape

Gene regulation plays a critical role in the evolution of phenotypic diversity. We investigated the evolution of liver promoters and enhancers in six primate species. We performed ChlP-seq for two histone modifications and RNA-seq to profile cis-regulatory element (CRE) activity and gene expression. The primate regulatory landscape is largely conserved across the lineage. Conserved CRE function is associated with sequence conservation, proximity to coding genes, cell type specificity of CRE function, and transcription factor binding. Newly evolved CREs are enriched in immune response and neurodevelopmental functions, while conserved CREs bind master regulators. Transposable elements (TEs) are the primary source of novelty in primate gene regulation. Newly evolved CREs are enriched in young TEs that affect gene expression. However, only 17% of conserved CREs overlap a TE, suggesting that target gene expression is under strong selection. Finally, we identified specific genomic features driving the functional recruitment of newly inserted TEs.

genomics↗