Single-cell mapping of lineage and identity in direct reprogramming

Nature. 2018 Dec;564(7735):219-224. doi: 10.1038/s41586-018-0744-4. Epub 2018 Dec 5.


Direct lineage reprogramming involves the conversion of cellular identity. Single-cell technologies are useful for deconstructing the considerable heterogeneity that emerges during lineage conversion. However, lineage relationships are typically lost during cell processing, complicating trajectory reconstruction. Here we present 'CellTagging', a combinatorial cell-indexing methodology that enables parallel capture of clonal history and cell identity, in which sequential rounds of cell labelling enable the construction of multi-level lineage trees. CellTagging and longitudinal tracking of fibroblast to induced endoderm progenitor reprogramming reveals two distinct trajectories: one leading to successfully reprogrammed cells, and one leading to a 'dead-end' state, paths determined in the earliest stages of lineage conversion. We find that expression of a putative methyltransferase, Mettl7a1, is associated with the successful reprogramming trajectory; adding Mettl7a1 to the reprogramming cocktail increases the yield of induced endoderm progenitors. Together, these results demonstrate the utility of our lineage-tracing method for revealing the dynamics of direct reprogramming.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage* / drug effects
  • Cell Separation
  • Cell Tracking / methods*
  • Cellular Reprogramming* / drug effects
  • Clone Cells / cytology*
  • Clone Cells / drug effects
  • Endoderm / cytology
  • Endoderm / drug effects
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • HEK293 Cells
  • Humans
  • Methyltransferases / metabolism
  • Mice
  • Single-Cell Analysis / methods*
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Time Factors


  • Methyltransferases
  • Mettl7a1 protein, mouse