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Transcriptional diversity during lineage commitment of human blood progenitors.

ABSTRACT: Blood cells derive from hematopoietic stem cells through stepwise fating events. To characterize gene expression programs driving lineage choice, we sequenced RNA from eight primary human hematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. We identified extensive cell type-specific expression changes: 6711 genes and 10,724 transcripts, enriched in non-protein-coding elements at early stages of differentiation. In addition, we found 7881 novel splice junctions and 2301 differentially used alternative splicing events, enriched in genes involved in regulatory processes. We demonstrated experimentally cell-specific isoform usage, identifying nuclear factor I/B (NFIB) as a regulator of megakaryocyte maturation-the platelet precursor. Our data highlight the complexity of fating events in closely related progenitor populations, the understanding of which is essential for the advancement of transplantation and regenerative medicine.

SUBMITTER: Chen L

PROVIDER: S-EPMC4254742 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Transcriptional diversity during lineage commitment of human blood progenitors.

Chen Lu L Kostadima Myrto M Martens Joost H A JHA Canu Giovanni G Garcia Sara P SP Turro Ernest E Downes Kate K Macaulay Iain C IC Bielczyk-Maczynska Ewa E Coe Sophia S Farrow Samantha S Poudel Pawan P Burden Frances F Jansen Sjoert B G SBG Astle William J WJ Attwood Antony A Bariana Tadbir T de Bono Bernard B Breschi Alessandra A Chambers John C JC Consortium Bridge B Choudry Fizzah A FA Clarke Laura L Coupland Paul P van der Ent Martijn M Erber Wendy N WN Jansen Joop H JH Favier Rémi R Fenech Matthew E ME Foad Nicola N Freson Kathleen K van Geet Chris C Gomez Keith K Guigo Roderic R Hampshire Daniel D Kelly Anne M AM Kerstens Hindrik H D HHD Kooner Jaspal S JS Laffan Michael M Lentaigne Claire C Labalette Charlotte C Martin Tiphaine T Meacham Stuart S Mumford Andrew A Nürnberg Sylvia S Palumbo Emilio E van der Reijden Bert A BA Richardson David D Sammut Stephen J SJ Slodkowicz Greg G Tamuri Asif U AU Vasquez Louella L Voss Katrin K Watt Stephen S Westbury Sarah S Flicek Paul P Loos Remco R Loos Remco R Goldman Nick N Bertone Paul P Read Randy J RJ Richardson Sylvia S Cvejic Ana A Soranzo Nicole N Ouwehand Willem H WH Stunnenberg Hendrik G HG Frontini Mattia M Rendon Augusto A

Science (New York, N.Y.) 20140901 6204

Blood cells derive from hematopoietic stem cells through stepwise fating events. To characterize gene expression programs driving lineage choice, we sequenced RNA from eight primary human hematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. We identified extensive cell type-specific expression changes: 6711 genes and 10,724 transcripts, enriched in non-protein-coding elements at early stages of differentiation. In addition, we found 7 ...[more]

PMID: 25258084

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Project description:Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Haematopoiesis provides a well-defined model to study epigenetic modifications during cell-fate decisions, as multipotent progenitors (MPPs) differentiate into progressively restricted myeloid or lymphoid progenitors. Although DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs, a comprehensive DNA methylation map of haematopoietic progenitors, or of any multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Marked epigenetic plasticity accompanied both lymphoid and myeloid restriction. Myeloid commitment involved less global DNA methylation than lymphoid commitment, supported functionally by myeloid skewing of progenitors following treatment with a DNA methyltransferase inhibitor. Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands. Many examples of genes and pathways not previously known to be involved in choice between lymphoid/myeloid differentiation have been identified, such as Arl4c and Jdp2. Several transcription factors, including Meis1, were methylated and silenced during differentiation, indicating a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome seems to be important in haematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation and defines a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions.

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Transcriptional diversity during lineage commitment of human blood progenitors.

Publications

Transcriptional diversity during lineage commitment of human blood progenitors.

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