Biology subjects

Lizio, M.

Publications and source records attributed to Lizio, M..

3 recordsLinked to original sources

bioRxiv2017

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Interestingly, although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed. In addition, a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and independent manner.

molecular biology↗

bioRxiv2017

Linking FANTOM5 CAGE Peaks To Annotations With CAGEscan

The FANTOM5 expression atlas is a quantitative measurement of the activity of nearly 200,000 promoter regions across nearly 2,000 different human primary cells, tissue types and cell lines. Generation of this atlas was made possible by the use of CAGE, an experimental approach to localise transcription start sites at single-nucleotide resolution by sequencing the 5' ends of capped RNAs after their conversion to cDNAs. While 50% of CAGE-defined promoter regions could be confidently associated to adjacent transcriptional units, nearly 100,000 promoter regions remained gene-orphan. To address this, we used the CAGEscan method, in which random-primed 5'-cDNAs are paired-end sequenced. Pairs starting in the same region are assembled in transcript models called CAGEscan clusters. Here, we present the production and quality control of CAGEscan libraries from 56 FANTOM5 RNA sources, which enhances the FANTOM5 expression atlas by providing experimental evidence associating core promoter regions with their cognate transcripts.

genomics↗

bioRxiv2016

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease.

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share patterns of transcriptional regulation. Accordingly, shared transcriptional regulation (coexpression) may help prioritise loci associated with a given trait, and help to identify the biological processes underlying it. Using cap analysis of gene expression (CAGE) profiles of promoter and enhancer-derived RNAs across 1824 human samples, we have quantified coexpression of RNAs originating from trait-associated regulatory regions using a novel analytical method (network density analysis; NDA). For most traits studied, sequence variants in regulatory regions were linked to tightly coexpressed networks that are likely to share important functional characteristics. These networks implicate particular cell types and tissues in disease pathogenesis; for example, variants associated with ulcerative colitis are linked to expression in gut tissue, whereas Crohns disease variants are restricted to immune cells. We show that this coexpression signal provides additional independent information for fine mapping likely causative variants. This approach identifies additional genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. This approach enables a deeper biological understanding of the causal basis of complex traits.\n\nONE SENTENCE SUMMARYWe discover that variants associated with a specific disease share expression profiles across tissues and cell types, enabling fine mapping and identification of new disease-associated variants, illuminating key cell types involved in disease pathogenesis.

genomics↗