Lineage tracing reveals fate bias and transcriptional memory in human B cells

We combined single-cell transcriptomics and lineage tracing to understand fate choice in human B cells. Using the antibody sequences of B cells, we tracked clones during in vitro differ-entiation. Clonal analysis revealed a subset of IgM+ B cells which were more proliferative than other B-cell types. Whereas the population of B cells adopted diverse states during differenti-ation, clones had a restricted set of fates available to them; there were two times more single-fate clones than expected given population-level cell-type diversity. This implicated a molecular memory of initial cell states that was propagated through dif-ferentiation. We then identified the genes which had strongest coherence within clones. These genes significantly overlapped known B-cell fate determination programs, suggesting the genes which determine cell identity are most robustly controlled on a clonal level. Persistent clonal identities were also observed in human plasma cells from bone marrow, indicating that these transcriptional programs maintain long-term cell identities in vivo. Thus, we show how cell-intrinsic fate bias influences dif-ferentiation outcomes in vitro and in vivo.