mBISON: Finding miRNA target over-representation in gene lists from ChIP-sequencing data.

BACKGROUND: Over-representation of predicted miRNA targets in sets of genes regulated by a given transcription factor (e.g. as defined by ChIP-sequencing experiments) helps to identify biologically relevant miRNA targets and is useful to get insight into post-transcriptional regulation. FINDINGS: To facilitate the application of this approach we have created the mBISON web-application. mBISON calculates the significance of over-representation of miRNA targets in a given non-ranked gene set. The gene set can be specified either by a list of genes or by one or more ChIP-seq datasets followed by a user-defined peak-gene association procedure. mBISON is based on predictions from TargetScan and uses a randomization step to calculate False-Discovery-Rates for each miRNA, including a correction for gene set specific properties such as 3'UTR length. The tool can be accessed from the following web-resource: http://cbdm.mdc-berlin.de/~mgebhardt/cgi-bin/mbison/home . CONCLUSION: mBISON is a web-application that helps to extract functional information about miRNAs from gene lists, which is in contrast to comparable applications easy to use by everyone and can be applied on ChIP-seq data directly.

PU.1 level-directed chromatin structure remodeling at the Irf8 gene drives dendritic cell commitment.

Dendritic cells (DCs) are essential regulators of immune responses; however, transcriptional mechanisms that establish DC lineage commitment are poorly defined. Here, we report that the PU.1 transcription factor induces specific remodeling of the higher-order chromatin structure at the interferon regulatory factor 8 (Irf8) gene to initiate DC fate choice. An Irf8 reporter mouse enabled us to pinpoint an initial progenitor stage at which DCs separate from other myeloid lineages in the bone marrow. In the absence of Irf8, this progenitor undergoes DC-to-neutrophil reprogramming, indicating that DC commitment requires an active, Irf8-dependent escape from alternative myeloid lineage potential. Mechanistically, myeloid Irf8 expression depends on high PU.1 levels, resulting in local chromosomal looping and activation of a lineage- and developmental-stage-specific cis-enhancer. These data delineate PU.1 as a concentration-dependent rheostat of myeloid lineage selection by controlling long-distance contacts between regulatory elements and suggest that specific higher-order chromatin remodeling at the Irf8 gene determines DC differentiation.