Concurrent stem- and lineage-affiliated chromatin programs precede hematopoietic lineage restriction.

Safi F, Dhapola P, Warsi S, Sommarin M, Erlandsson E, Ungerbäck J, Warfvinge R, Sitnicka E, Bryder D, Böiers C, Thakur RK, Karlsson G

Cell Rep 39 (6) 110798 [2022-05-10; online 2022-05-12]

The emerging notion of hematopoietic stem and progenitor cells (HSPCs) as a low-primed cloud without sharply demarcated gene expression programs raises the question on how cellular-fate options emerge and at which stem-like stage lineage priming is initiated. Here, we investigate single-cell chromatin accessibility of Lineage-, cKit+, and Sca1+ (LSK) HSPCs spanning the early differentiation landscape. Application of a signal-processing algorithm to detect transition points corresponding to massive alterations in accessibility of 571 transcription factor motifs reveals a population of LSK FMS-like tyrosine kinase 3 (Flt3)intCD9high cells that concurrently display stem-like and lineage-affiliated chromatin signatures, pointing to a simultaneous gain of both lympho-myeloid and megakaryocyte-erythroid programs. Molecularly and functionally, these cells position between stem cells and committed progenitors and display multi-lineage capacity in vitro and in vivo but lack self-renewal activity. This integrative molecular analysis resolves the heterogeneity of cells along hematopoietic differentiation and permits investigation of chromatin-mediated transition between multipotency and lineage restriction.

Clinical Genomics Lund [Service]

PubMed 35545037

DOI 10.1016/j.celrep.2022.110798

Crossref 10.1016/j.celrep.2022.110798

pii: S2211-1247(22)00565-4