Deconvolution of Hematopoietic Commitment Decisions By Genome-Wide Analysis of Progressive DNA Methylation Changes

Recent advances in single cell transcriptome analyses have resulted in the derivation of new models to describe the hierarchical organization of the mammalian hematopoietic system. While such an approach appears to be effective at discerning the trajectory of differentiation from hematopoietic stem...

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Published in:Blood 2019-11, Vol.134 (Supplement_1), p.1179-1179
Main Authors: Staeble, Sina, Kraemer, Stephen, Langstein, Jens, Bogeska, Ruzhica, Hartmann, Mark, Schoenung, Maximilian, Czeh, Melinda, Knoch, Julia, Anstee, Natasha, Haas, Simon, Mahmoud, Abdelrahman, Graesel, Julius, Huebschmann, Daniel, Feuerbach, Lars, Dieter, Weichenhan, Brors, Benedikt, Rippe, Karsten, Mallm, Jan-Philipp, Rosenbauer, Frank, Plass, Christoph, Schlesner, Matthias, Milsom, Michael D., Lipka, Daniel B.
Format: Article
Language:English
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Summary:Recent advances in single cell transcriptome analyses have resulted in the derivation of new models to describe the hierarchical organization of the mammalian hematopoietic system. While such an approach appears to be effective at discerning the trajectory of differentiation from hematopoietic stem cells (HSCs) to a given mature lineage, it remains a challenge to identify definitive points where specific lineage fates become restricted. The characterization of molecular events that correspond to such commitment decisions is critical to our interrogation of the existence and nature of serial bifurcation steps that are hypothesized to underlie the process of hematopoiesis. 5-Methylcytosine is a stable epigenetic modification, whose remodeling at specific CpG residues appears to be integral to the process of enforcing lineage-restricted gene expression programs. We have previously observed that the remodeling of the DNA methylome appears to be both progressive and irreversible during the process of hematopoietic differentiation, suggesting that this modification could be used to unambiguously identify molecular marks of lineage commitment. In order to pursue this concept further, we used tagmentation-based whole-genome bisulfite sequencing to generate a genome-wide DNA methylation map of murine hematopoiesis. This map encompasses 26 different FACS-purified populations, ranging from LT-HSCs through to terminally differentiated blood cell lineages. Across all cell populations studied, we identified 147,232 differentially methylated regions (DMRs). In line with our previous data, hierarchical clustering of these DMRs revealed coordinately regulated regions that show progressive and unidirectional lineage-specific DNA methylation dynamics during hematopoietic differentiation that would be indicative of a molecular mechanism of cell fate restriction. Single cell DNA methylome analysis indicated that methylation programming may be exclusive for a specific lineage within each cell analyzed, supporting the use of this data to establish the discreet points at which lineage commitment occurs. Along these lines, lineage-specific DMRs could already be identified within the early hematopoietic stem and multipotent progenitor compartments, supporting the concept that lineage restriction occurs early during differentiation and providing a potential molecular basis for so called lineage-priming/bias. Indeed, a phylogenetic tree of the entire hematopoietic system could be con
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2019-124429