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

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 521 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 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 trajectories, and permits investigation of chromatin-mediated transition between multipotency and lineage restriction.

ORGANISM(S): Mus musculus

PROVIDER: GSE148746 | GEO | 2022/05/02

REPOSITORIES: GEO

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Project description:Hematopoiesis is a well-established model system to study molecular mechanisms of lineage-specific differentiation. Key transcription factors (TFs), such as PU.1, NF-E2 and GATA1 are implicated in crucial aspects of distinct hematopoietic lineages. How TFs collaborate with histone modificatons and how they affect the chromatin status remains to be elucidated. Chromatin-Immunoprecipitation followed by next-generation sequencing (ChIP-seq) has been proven to be an excellent tool to study chromatin modifications genome-wide. In this study, ChIP-seq was used to investigate the H3K4me2 landscape at enhancers during hematopoietic differentiation, starting from the hematopoietic stem cell (HSC) up to the fully differentiated erythrocyte, megakaryocyte or granulocyte. Although cell morphology and gene expression profiles differ extensively in committed erythrocytes, megakaryocytes and granulocytes, the genomic landscape of H3K4me2 is surprisingly alike across the three cell types. Granulocytes, in particular, seem to display an ‘erythocyte-like’ chromatin pattern. Similar results were observed for another chromatin mark, H3K27ac. Unexpectedly, the common progenitors of erythrocytes and granulocytes do not display a similar chromatin pattern, excluding the idea that the H3K4me2 mark is placed early on during differentiation. These results also suggest that the chromatin state is probably not the determining factor for lineage differentiation, but that rather lineage specific TF binding is important. In agreement with this, mature megakaryocytes loose the H3K4me2 mark surrounding erythrocyte-specific genes. This might be explained because megakaryocytes and erythrocytes both express the lineage specific TFs GATA1 and NF-E2. Altogether, we show that committed granulocytes and erythrocytes display similar H3K4me2 and H3K27ac patterns, and that those marks alone cannot predict which genes will be expressed eventually. Genomic ChIP-Seq on key transcription factors and histone modification marks in hematopoiesis

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

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