An integrated expression atlas of miRNAs and their promoters in human and mouse

By applying short RNA-sequencing and Cap Analysis of Gene Expression (CAGE) we have generated expression profiles of mature miRNAs and their primary transcripts across a large collection of primary cell types. CAGE has also allowed us to map their promoters. We show that miRNA promoters are highly conserved, that the expression profiles of the mature and the primary transcript are correlated and that miRNAs originating from the same polycistron are highly correlated. We present the data as a web resource to the research community.

De Rie D., et al. Nature Biotechnology
DOI: 10.1038/nbt.3947
Full Text

An atlas of human long non-coding RNAs with accurate 5′ ends

There is a strong debate on whether the thousands of long non-coding RNAs transcribed from our genomes are functional or simply byproducts of a noisy transcriptional machinery. Scientists from the RIKEN-led FANTOM5 consortium used a technology known as Cap Analysis of Gene Expression (CAGE) to build an atlas of human long non-coding RNAs with accurate 5’ ends and summarized their expression patterns across the major cell types. In the work, published in Nature, they intersected this expression atlas with other genetic and genomic datasets and suggested many of these long non-coding RNAs might be functional.

Hon C., et al. Nature
DOI: 10.1038/nature21374
Full Text

Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells.

Exploiting the fact that active promoters and enhancers are transcribed, we simultaneously measured their activity in 19 human and 14 mouse time courses covering a wide range of cell types and biological stimuli. Our analysis suggests a highly generalizable model in which enhancer transcription is the earliest event in successive waves of transcriptional change during cellular differentiation or activation.

Arner E., et al. Science
DOI: 10.1126/science.1259418
Full Text

Promoter and enhancer atlases across the human body

Promoter (blue) and enhancer (red) densities across human chromosomes. Chromosome 5 is expanded showing promoter cell specificity/expression (pink/yellow outer layers), corresponding enhancer data (inner layers) and enhancer-promoter interactions (blue). Co-expression clusters between promoters are shown as colored lines between chromosomes.

Image by Robin Andersson and Albin Sandelin

A promoter level mammalian expression atlas.

Cap Analysis of Gene Expression (CAGE) across a large collection of primary cell types has revealed many mammalian promoters are composite entities composed of multiple closely-separated TSS, with independent cell-type-specific expression profiles. The FANTOM5 promoter centric expression atlas provides expression profiles for the majority of coding and non-coding transcripts in the human and mouse genomes.

Forrest, A.R.R. et al. Nature
DOI: 10.1038/nature13182

An atlas of active enhancers across the human body.

Enhancers control the correct temporal and cell-type-specific activation of gene expression. We have made an atlas of active enhancers across the majority of human tissues and cell types. The atlas is used to compare regulatory programs between different cells, to identify disease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific and ubiquitous enhancers.

Andersson, R. et al. Nature
DOI: 10.1038/nature12787

Redefinition of the human mast cell transcriptome by deep sequencing.

Using freshly isolated skin-derived Mast cells (MCs) FANTOM5 reveals a comprehensive view of the human MC transcriptome. Mast cells are unique in the hematopoietic lineage and are only distantly related to basophils. We also show that mast cells express BMP receptors and that BMPs can promote survival and recovery to stimulation of human MCs.

Motakis, E. et al. Blood
DOI: 10.1182/blood-2013-02-483792

Transcription and enhancer profiling in human monocyte subsets.

Complementary CAGE and epigenetic profiling dissects differences between the three major subpopulations of human monocytes. This FANTOM5 study highlights differential gene, transcription factor and enhancer usage and identifies previously unrecognized metabolic differences between subpopulations.

Schmidl, C. et al. Blood
DOI: 10.1182/blood-2013-02-484188

The enhancer and promoter landscape of human regulatory and conventional T cell subpopulations.

Their ability to avert immune reactions makes regulatory T cells (Treg) highly interesting for clinical application. This FANTOM5 study investigates transcription factor networks in naïve and memory Treg and their conventional T cell (Tconv) counterparts both before and after in vitro expansion and shows that in vitro expanded Treg do not dramatically change their Treg-specific effector molecule repertoire.

Schmidl, C. et al. Blood
DOI: 10.1182/blood-2013-02-486944

Analysis of the DNA methylome and transcriptome in granulopoiesis reveals timed changes and dynamic enhancer methylation

Overall this study depicts in detail the epigenetic and transcriptional changes that occur during granulopoiesis and supports the role of DNA methylation as a regulatory mechanism in blood cell differentiation. We show that methylation change at specific differentiation stages and overlap with the activity of key hematopoietic transcription factors. Also, differentially methylated sites were overrepresented in enhancer elements and enriched in enhancers that become active during differentiation.

Rönnerblad et al. Blood
DOI: 10.1182/blood-2013-02-482893

High-throughput transcription profiling identifies putative epigenetic regulators of hematopoiesis

The transcriptional program that dictates hematopoietic cell fate and differentiation requires an epigenetic memory function provided by a network of epigenetic factors regulating DNA methylation, posttranslational histone modifications, and chromatin structure. To elucidate the contributions of different epigenetic factors in human hematopoiesis, high-throughput cap analysis of gene expression was used to build transcription profiles of 199 epigenetic factors in a wide range of blood cells.

Prasad et al. Blood
DOI: 10.1182/blood-2013-02-483537

Comparison of CAGE and RNA-seq transcriptome profiling using a clonally amplified and single molecule next generation sequencing

Kawaji et al. Genome Research
DOI: 10.1101/gr.156232.113

Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation.

Regulatory T (Treg) cells, which specifically express the transcription factor Foxp3, are engaged in the maintenance of immunological self-tolerance and homeostasis. Analysis of FANTOM5 CAGE data with epigenome data including DNA methylation and Transcription factor binding sites reveals that Treg specific demethylation and Foxp3 appear to play distinct but complementary roles in Treg specific gene regulation.

Morikawa H, et al. Proc Natl Acad Sci USA.
DOI: 10.1073/pnas.1312717110

The Evolution of Human Cells in terms of Protein Innovation

Combining FANTOM5 CAGE data and protein domain annotation we are able to get a view on how different cell types have evolved. We are able to identify known evolutionary events as well highlight other novel events that until know have remained undetected.

Sardar, A. J. et al. Molecular Biology and Evolution
DOI: 10.1093/molbev/mst139

Interactive visualization and analysis of large-scale NGS data-sets using ZENBU.

Next generation sequencing protocols such as RNA-seq, ChIP-seq, DHS-seq and CAGE across large sample collections are generating a wealth of data to elucidate genomic function. To facilitate interactive comparison of results across 1000s of NGS experiments we present ZENBU, a web application combining data integration, and data analysis into a genome browser with enhanced gene expression and epigenomic visualization capabilities.

Severin, J. et al. Nature Biotechnology
DOI: 10.1038/nbt.2840

Transcriptional profiling of the human fibrillin/LTBP gene family, key regulators of mesenchymal cell functions.

The fibrillins and latent transforming growth factor binding proteins (LTBPs) form a superfamily of proteins involved in the structure of the extracellular matrix and in controlling the bioavailability of TGFβ family members. We present a study of transcription start sites, which suggests this important class of extracellular matrix proteins is subject to subtle regulatory variations that explain the differential roles of members of this gene family.

Davis, M. R. et al. Molecular Genetics and Metabolism
DOI: 10.1016/j.ymgme.2013.12.006

Explaining the correlations among properties of mammalian promoters

Promoters have mysterious variation in CpG richness, TATA signals, evolutionary conservation, expression specificity, and chromosomal spread of transcription start sites. We warn of biases in measuring these properties, show that most promoters have rather non-specific expression, and provide simple explanations for the correlations among the properties.

Frith, M. C. et al. Nucleic Acids Research
DOI: 10.1093/nar/gku115

CAGExploreR: an R package for the analysis and visualization of promoter dynamics across multiple experiments.

CAGExploreR is an R package that facilitates the detection and visualization of changes in the relative transcription from promoter regions in multi-promoter genes, all in the context of overall gene expression. Multiple samples can be compared simultaneously. Primarily based on the FANTOM5 promoter set definitions, however other regions such as MPromDb or user-supplied regions can also be used.

Dimont, E. et al. Bioinformatics
DOI: 10.1093/bioinformatics/btu125

Ceruloplasmin is a novel adipokine which is overexpressed in adipose tissue of obese subjects and in obesity-associated cancer cells

Obesity confers an increased risk of developing specific cancer forms. Increased fat cell secretion of adipokines may promote malignant tumors in obesity via tissue cross-talk. We found ceruloplasmin (CP) expression to be strongly enriched in obesity-associated cancer, and in adipose tissue of obese subjects. We demonstrate that CP is a novel adipokine, with increased production and secretion in obesity.

Arner, E. et al. PLOS ONE
DOI: 10.1371/journal.pone.0080274

Effects of cytosine methylation on transcription factor binding sites

Methylation of 16% of individual CpGs negatively correlates with neighboring TSS expression. We observed a selection against these CpGs within transcription factor binding sites (TFBSs), being stronger for repressors than for activators, as well as for core TFBS positions than for flanking ones. We suggested that selective methylation of TFBSs preventing transcription factor binding is restricted to special cases and cannot be a global mechanism for transcription regulation.

Medvedeva Y.A. et al. BMC genomics
DOI: 10.1186/1471-2164-15-119

Chromatin states reveal functional associations for globally defined transcription start sites in four human cell lines

Deciphering the most common modes by which chromatin regulates transcription is an important task for improving our understanding of human cellular biology. Transcriptional data from FANTOM5 is integrated data from the ENCODE project to characterize chromatin features around expressed and repressed transcription start sites in four human cell lines.

Rye M. et al. BMC Genomics
DOI: 10.1186/1471-2164-15-120