Gene expression data are accumulating exponentially in public repositories. Reanalysis and integration of themed collections from these studies may provide new insights, but requires further human curation.Here we report a crowdsourcing project to annotate and reanalyse a large number of gene expression profiles from Gene Expression Omnibus (GEO). Through a massive open online course on Coursera, over 70 participants from over 25 countries identify and annotate 2,460 single-gene perturbation signatures, 839 disease versus normal signatures, and 906 drug perturbation signatures. All these signatures are unique and are manually validated for quality. Global analysis of these signatures confirms known associations and identifies novel associations between genes, diseases and drugs. The manually curated signatures are used as a training set to develop classifiers for extracting similar signatures from the entire GEO repository. We develop a web portal to serve these signatures for query, download and visualization.

SummaryPharmacologic inhibition of LSD1 promotes blast cell differentiation in acute myeloid leukemia (AML) with MLL translocations. The assumption has been that differentiation is induced through blockade of LSD1’s histone demethylase activity. However, we observed that rapid, extensive, drug-induced changes in transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein. Rather, LSD1 inhibitors disrupt the interaction of LSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1, which is bound to a discrete set of enhancers located close to transcription factor genes that regulate myeloid differentiation. Physical separation of LSD1/RCOR1 from GFI1 is required for drug-induced differentiation. The consequent inactivation of GFI1 leads to increased enhancer histone acetylation within hours, which directly correlates with the upregulation of nearby subordinate genes.

and has received compensation from these companies in the form of stock; A.R.K. is a research collaborator of Ionis Pharmaceuticals and has received royalty income from Ionis through his employer, Cold Spring Harbor Laboratory. O.A.-W. has served as a consultant for H3 Biomedicine, Foundation Medicine Inc., Merck, and Janssen; O.A.-W. has received personal speaking fees from Daiichi Sankyo. O.A.-W. has received prior research funding from H3 Biomedicine unrelated to the current manuscript. D.I., R.K.B. and O.A.-W. are inventors on a provisional patent application (patent number FHCC.P0044US.P) applied for by Fred Hutchinson Cancer Research Center on the role of reactivating BRD9 expression in cancer by modulating aberrant BRD9 splicing in SF3B1 mutant cells.