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

Safi, F.; Dhapola, P.; Warsi, S.; Erlandsson, E.; Sitnicka, E.; Bryder, D.; Boiers, C.; Thakur, R. K.; Karlsson, G.

doi:10.1101/2020.04.29.069062

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bioRxiv · 10.1101/2020.04.29.069062

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

Safi, F.·Dhapola, P.·Warsi, S.·Erlandsson, E.·Sitnicka, E.·Bryder, D.·Boiers, C.·Thakur, R. K.·Karlsson, G.

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Abstract

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 investigated single-cell chromatin accessibility of Lineage-, cKit+, 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 revealed 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, 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.

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Safi, F., Dhapola, P., Warsi, S., Erlandsson, E., Sitnicka, E., Bryder, D., Boiers, C., Thakur, R. K., Karlsson, G.. 2020-05-01. Concurrent stem- and lineage-affiliated chromatin programs precede hematopoietic lineage restriction. https://doi.org/10.1101/2020.04.29.069062

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