Olsson, A. et al. Nature 537, 698–702 (2016).

How a cell chooses between two fates is a fundamental question in development. Using single-cell RNA sequencing to identify cell states, Olsson et al. identified bifurcation points and inferred the regulatory genes that underlie cellular decisions. They developed an iterative clustering and guide-gene selection (ICGS) tool to find dynamically expressed genes and to identify expression patterns by clustering with pattern-specific 'guide genes'. Using RNA sequences generated from single blood cells, ICGS automatically resolved nine known myelopoiesis cell states. The authors' analysis reveals both common and rare (metastable) mixed-lineage states, as well as evidence for antagonistic relationships between regulatory genes from competing lineages. They show that a rare intermediate that gives rise to hematopoietic stem cell/progenitor and myeloid lineages could be trapped through elimination of the myeloid determinants IRF8 and GFI1.