Aberrant cell signaling can cause cancer and other diseases and is a focal point of drug research. A common approach is to infer signaling activity of pathways from gene expression. However, mapping gene expression to pathway components disregards the effect of post-translational modifications, and downstream signatures represent very specific experimental conditions. Here we present PROGENy, a method that overcomes both limitations by leveraging a large compendium of publicly available perturbation experiments to yield a common core of Pathway RespOnsive GENes. Unlike pathway mapping methods, PROGENy can (i) recover the effect of known driver mutations, (ii) provide or improve strong markers for drug indications, and (iii) distinguish between oncogenic and tumor suppressor pathways for patient survival. Collectively, these results show that PROGENy accurately infers pathway activity from gene expression in a wide range of conditions.
G.H. contributed to the study design and collection and interpretation of the data. R.P.K. performed the analysis of Circle-seq and whole-genome sequencing. E.R.F. performed the data analysis of the whole-genome sequencing data. I.
Developmental deconvolution of complex organs and tissues at the level of
individual cells remains challenging. Non-invasive genetic fate mapping1 has been widely used, but the low number
of distinct fluorescent marker proteins limits its resolution. Much higher
numbers of cell markers have been generated using viral integration sites2, viral barcodes3, and strategies based on transposons4 and CRISPR/Cas9 genome editing5; however, temporal and tissue-specific induction of
barcodes in situ has not been achieved. Here we report the development of an
artificial DNA recombination locus (termed Polylox) that
enables broadly applicable endogenous barcoding based on the
Cre-loxP recombination system6,7. Polylox
recombination in situ reaches a practical diversity of several hundred thousand
barcodes, allowing tagging of single cells. We have used this experimental
system, combined with fate mapping, to assess haematopoietic stem cell (HSC)
fates in vivo. Classical models of haematopoietic lineage specification assume a
tree with few major branches. More recently, driven in part by the development
of more efficient single-cell assays and improved transplantation efficiencies,
different models have been proposed, in which unilineage priming may occur in
mice and humans at the level of HSCs8–10. We have
introduced barcodes into HSC progenitors in embryonic mice, and found that the
adult HSC compartment is a mosaic of embryo-derived HSC clones, some of which
are unexpectedly large. Most HSC clones gave rise to multilineage or
oligolineage fates, arguing against unilineage priming, and suggesting coherent
usage of the potential of cells in a clone. The spreading of barcodes, both
after induction in embryos and in adult mice, revealed a basic split between
common myeloid-erythroid development and common lymphocyte development,
supporting the long-held but contested view of a tree-like haematopoietic
structure.
Mass spectrometry has become an important analytical tool in biology in the past two decades. In principle, mass spectrometry offers high-throughput, sensitive and specific analysis for many applications in microbiology, including clinical diagnostics and environmental research. Recently, several mass spectrometry methods for the classification and identification of bacteria and other microorganisms, as well as new software analysis tools, have been developed. In this Review we discuss the application range of these mass spectrometry procedures and their potential for successful transfer into microbiology laboratories.
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