Abstract
Transcription factors are key regulators of both normal and malignant hematopoiesis. Chromatin immunoprecipitation (ChIP) coupled with high-throughput sequencing (ChIP-Seq) has become the method of choice to interrogate the genome-wide effect of transcription factors. We have collected and integrated 142 publicly available ChIP-Seq datasets for both normal and leukemic murine blood cell types. In addition, we introduce the new bioinformatic tool Gene Set Control Analysis (GSCA). GSCA predicts likely upstream regulators for lists of genes based on statistical significance of binding event enrichment within the gene loci of a user-supplied gene set. We show that GSCA analysis of lineage-restricted gene sets reveals expected and previously unrecognized candidate upstream regulators. Moreover, application of GSCA to leukemic gene sets allowed us to predict the reactivation of blood stem cell control mechanisms as a likely contributor to LMO2 driven leukemia. It also allowed us to clarify the recent debate on the role of Myc in leukemia stem cell transcriptional programs. As a result, GSCA provides a valuable new addition to analyzing gene sets of interest, complementary to Gene Ontology and Gene Set Enrichment analyses. To facilitate access to the wider research community, we have implemented GSCA as a freely accessible web tool (http://bioinformatics.cscr.cam.ac.uk/GSCA/GSCA.html).
Highlights
Transcription factors are key regulators of both normal and malignant hematopoiesis
Definition of a candidate regulatory genome in mouse hematopoiesis We recently reported a compendium of more than 50 transcription factor (TF) Chromatin immunoprecipitation (ChIP)-Seq experiments in mouse blood cells collected from publicly available datasets [8]
A new Gene Set Control Analysis (GSCA) tool matches weighted TF-peak lists to gene sets We explored whether our blood-specific TF ChIP-Seq peak catalogue could be used to predict transcriptional control mechanisms that may regulate the coordinated expression of a given set of genes
Summary
Transcription factors are key regulators of both normal and malignant hematopoiesis. Chromatin immunoprecipitation (ChIP) coupled with high-throughput sequencing (ChIP-Seq) has become the method of choice to interrogate the genome-wide effect of transcription factors. Application of GSCA to leukemic gene sets allowed us to predict the reactivation of blood stem cell control mechanisms as a likely contributor to LMO2 driven leukemia. Identification of control mechanisms in normal cells provides potential avenues for manipulating cellular fates, as exemplified by the recent explosion in cellular reprogramming studies [1] It enables the rational design of new therapies. The technique has been rapidly adopted with over 100 individual studies deposited in public databases for the murine hematopoietic system alone This wealth of new data represents unprecedented opportunities to unravel the transcriptional control mechanisms that mediate expression of specific sets of genes within the various hematopoietic cell lineages [8]
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