Memory of Divisional History Directs the Continuous Process of Primitive Hematopoietic Lineage Commitment
| Autor: | Alexander Lachmann, Dmitrii Shcherbinin, Avinash Waghray, Dmitri Papatsenko, Ran Brosh, Kateri A. Moore, Jeffrey M. Bernitz, Avi Ma'ayan, Ye Yuan, Andreia Gomes, Michael G. Daniel, Katrina Rapp |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male cell heterogeneity Priming (immunology) macromolecular substances Biochemistry Models Biological Article hematopoietic stem cells divisional history polycomb repressive complex epigenetics memory leukemia memory 03 medical and health sciences 0302 clinical medicine Genetics Animals Homeostasis Cell Lineage Enhancer of Zeste Homolog 2 Protein Epigenetics Cell Self Renewal Gene Transcription factor biology epigenetics Polycomb Repressive Complex 2 RNA Cell Biology Chromatin Cell biology Hematopoiesis Mice Inbred C57BL Haematopoiesis 030104 developmental biology Gene Expression Regulation biology.protein Female Stem cell PRC2 030217 neurology & neurosurgery Cell Division Developmental Biology |
| Zdroj: | Stem Cell Reports Stem Cell Reports, 14 (4) |
| DOI: | 10.3929/ethz-b-000463404 |
| Popis: | Summary Hematopoietic stem cells (HSCs) exist in a dormant state and progressively lose regenerative potency as they undergo successive divisions. Why this functional decline occurs and how this information is encoded is unclear. To better understand how this information is stored, we performed RNA sequencing on HSC populations differing only in their divisional history. Comparative analysis revealed that genes upregulated with divisions are enriched for lineage genes and regulated by cell-cycle-associated transcription factors, suggesting that proliferation itself drives lineage priming. Downregulated genes are, however, associated with an HSC signature and targeted by the Polycomb Repressive Complex 2 (PRC2). The PRC2 catalytic subunits Ezh1 and Ezh2 promote and suppress the HSC state, respectively, and successive divisions cause a switch from Ezh1 to Ezh2 dominance. We propose that cell divisions drive lineage priming and Ezh2 accumulation, which represses HSC signature genes to consolidate information on divisional history into memory. Graphical Abstract Highlights • Divisional history is a major source of gene expression variation across HSCs • Cell divisions themselves appear to drive lineage priming in HSCs • Comparative analysis suggests that chromatin marks are dynamic with cell divisions • An Ezh1-to-Ezh2 switch consolidates HSC divisional history information into memory Separating the HSC population by divisional history shows patterned expression changes across the divisional history spectrum indicating that lineage priming and differentiation are functions of cell divisions themselves. Comparative analysis of gene expression, chromatin, and knockout studies reveal that an epigenetic switch from Ezh1 to Ezh2 underlies HSC functional decline with successive divisions and stores HSC memory of its divisional past. |
| Databáze: | OpenAIRE |
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