Biology subjects

Andersson, R.

Publications and source records attributed to Andersson, R..

5 recordsLinked to original sources

bioRxiv2018

The GBAF chromatin remodeling complex binds H3K27ac and mediates enhancer transcription

H3K27ac is associated with regulatory active enhancers, but its exact role in enhancer function remains elusive. Using mass spectrometry-based interaction proteomics, we identified the Super Elongation Complex (SEC) and GBAF, a non-canonical GLTSCR1L- and BRD9-containing SWI/SNF chromatin remodeling complex, to be major interactors of H3K27ac. We systematically characterized the composition of GBAF and the conserved GLTSCR1/1L GiBAF-domain, which we found to be responsible for GBAF complex formation and GLTSCR1L nuclear localization. Inhibition of the bromodomain of BRD9 revealed interaction between GLTSCR1L and H3K27ac to be BRD9-dependent and led to GLTSCR1L dislocation from its preferred binding sites at H3K27ac-associated enhancers. GLTSCR1L disassociation from chromatin resulted in genome-wide downregulation of enhancer transcription while leaving most mRNA expression levels unchanged, except for reduced mRNA levels from loci topologically linked to affected enhancers. Our results indicate that GBAF is an enhancer-associated chromatin remodeler important for transcriptional and regulatory activity of enhancers.\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=142 HEIGHT=200 SRC=\"FIGDIR/small/445148_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (32K):\norg.highwire.dtl.DTLVardef@10c54dborg.highwire.dtl.DTLVardef@9730dforg.highwire.dtl.DTLVardef@9985eorg.highwire.dtl.DTLVardef@1f26844_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2018

CAGEfightR: Cap Analysis of Gene Expression (CAGE) in R/Bioconductor

We developed the CAGEfightR R/Biconductor-package for analyzing CAGE data. CAGEfightR allows for fast and memory efficient identification of transcription start sites (TSSs) and predicted enhancers. Downstream analysis, including annotation, quantification, visualization and TSS shape statistics are implemented in easy-to-use functions. The package is freely available at https://bioconductor.org/packages/CAGEfightR

bioinformatics↗

bioRxiv2017

Transcription start site analysis reveals widespread divergent transcription in D. melanogaster and core promoter encoded enhancer activities

Mammalian gene promoters and enhancers share many properties. They are composed of a unified promoter architecture of divergent transcripton initiation and gene promoters may exhibit enhancer function. However, it is currently unclear how expression strength of a regulatory element relates to its enhancer strength and if the unifying architecture is conserved across Metazoa. Here we investigate the transcription initiation landscape and its associated RNA decay in D. melanogaster. Surprisingly, we find that the majority of active gene-distal enhancers and a considerable fraction of gene promoters are divergently transcribed. We observe quantitative relationships between enhancer potential, expression level and core promoter strength, providing an explanation for indirectly related histone modifications that are reflecting expression levels. Lowly abundant unstable RNAs initiated from weak core promoters are key characteristics of gene-distal developmental enhancers, while the housekeeping enhancer strengths of gene promoters reflect their expression strengths. The different layers of regulation mediated by gene-distal enhancers and gene promoters are also reflected in chromatin interaction data. Our results suggest a unified promoter architecture of many D. melanogaster regulatory elements, that is universal across Metazoa, whose regulatory functions seem to be related to their core promoter elements.

genomics↗

bioRxiv2017

Transcriptional decomposition reveals active chromatin architectures and cell specific regulatory interactions

Transcriptional regulation is tightly coupled with chromosomal positioning and three-dimensional chromatin architecture. However, it is unclear what proportion of transcriptional activity is reflecting such organisation, how much can be informed by RNA expression alone, and how this impacts disease. Here, we develop a transcriptional decomposition approach separating the proportion of expression associated with genome organisation from independent effects not directly related to genomic positioning.\n\nWe show that positionally attributable expression accounts for a considerable proportion of total levels and is highly informative of topological associating domain activities and organisation, revealing boundaries and chromatin compartments. Furthermore, expression data alone accurately predicts individual enhancer-promoter interactions, drawing features from expression strength, stabilities, insulation and distance. We further characterise commonalities and differences across predictions in 76 human cell types, observing extensive sharing of domains, yet highly cell-type specific enhancer-promoter interactions and strong enrichments in relevant trait-associated variants. Our work demonstrates a close relationship between transcription and chromatin architecture, presenting a novel strategy and an unprecedented resource for investigating regulatory organisations and interpretations of disease associated genetic variants across cell types.

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↗