An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis.

Thousands of epigenomic data sets have been generated in the past decade, but it is difficult for researchers to effectively use all the data relevant to their projects. Systematic integrative analysis can help meet this need, and the VISION project was established for validated systematic integration of epigenomic data in hematopoiesis. Here, we systematically integrated extensive data recording epigenetic features and transcriptomes from many sources, including individual laboratories and consortia, to produce a comprehensive view of the regulatory landscape of differentiating hematopoietic cell types in mouse. By using IDEAS as our integrative and discriminative epigenome annotation system, we identified and assigned epigenetic states simultaneously along chromosomes and across cell types, precisely and comprehensively. Combining nuclease accessibility and epigenetic states produced a set of more than 200,000 candidate cis-regulatory elements (cCREs) that efficiently capture enhancers and promoters. The transitions in epigenetic states of these cCREs across cell types provided insights into mechanisms of regulation, including decreases in numbers of active cCREs during differentiation of most lineages, transitions from poised to active or inactive states, and shifts in nuclease accessibility of CTCF-bound elements. Regression modeling of epigenetic states at cCREs and gene expression produced a versatile resource to improve selection of cCREs potentially regulating target genes. These resources are available from our VISION website to aid research in genomics and hematopoiesis.National Institute of Diabetes and Digestive and Kidney Diseases (grant number R24DK106766-01A1), the National Human Genome Research Institute (grant number U54HG006998

Biofilm formation of <i>A. xylosoxidans</i> NH44784-1996.

<p>A: 3 day old biofilm grown in flow cell system and visualized by scanning confocal laser microscopy. Syto 9 was injected 15 min. before examination to stain for the presence of living cells. B: 2 day old biofilm grown under static condition investigated with SEM.</p

Drug resistance systems.

<p>A comparison of drug resistance systems as annotated by RAST between <i>A. xylosoxidans</i> NH44784-1996 and 10 other pathogens. The classification is divided in following groups: ‘antibiotic resistance’, ‘metal resistance’ and ‘other resistance’ according to RAST.</p

Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes.

Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state Regulatory Potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbored distinctive transcription factor binding motifs that were similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we showed that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.NI

A circular view of the genome of <i>A. xylosoxidans</i> NH44784-1996.

<p>Including CDS and RNA features, GC content and skew. The figure was prepared using CGView [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068484#B97" target="_blank">97</a>]. A genome-genome comparison with <i>A. xylosoxidans</i> A8 (CP002287 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068484#B40" target="_blank">40</a>]) was created using MegaBlast with default parameters.</p

The 11 most related bacterial strains to <i>A. xylosoxidans</i> NH44784-1996 investigated by BLASTP search.

<p>The numbers are referring to open reading frames.</p

Comparison of the amount of genes connected to subsystems.

<p>Number of genes of <i>A. xylosoxidans</i> NH44784-1996, <i>E. coli</i> K-12 and <i>P. aeruginosa</i> PAO1 connected to the different subsystems in The RAST software.</p

Phylogenetic tree.

<p>Neighbor-joining dendrogram showing the relationship of NH44784-1996 and 77 <i>Achromobacter</i> strains, using <i>B</i><i>. petrii</i> DSM 12804 as an outgroup. The comparison was based on the concatenated sequences of MLSA genes <i>atpD</i>, <i>icd</i>, <i>recA</i>, <i>rpoB</i> and <i>tyrB</i> (2,098 nt). MLSA clusters I–V are shown. Bootstrap support of clusters is indicated to the left of the node. Scale bar, 0.01 substitutions per site.</p