Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 218, Issue 10, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20202317
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Funding
- Agence Nationale de la Recherche (ANR) [ANR-11-BSV3-018-01, ANR-17-CE15-0023-01]
- Institut National du Cancer (INCa) [PLBIO2015-114]
- Ligue Nationale Contre le Cancer (LNCC)
- Fondation pour la Recherche Medicale (FRM
- Equipe FRM 2019) [EQU201903007812]
- Fondation ARC
- LNCC Grand Est/Bourgogne Franche Comte
- INSERM
- CNRS
- Universite de Strasbourg
- ANR [ANR-17-CE15-0023-01, ANR-10-LABX-0030-INRT, ANR-10-IDEX-0002-02]
- LNCC Grand Est/Bourgogne Franche Comte equipment grant [001K.2016]
- IGBMC International PhD Programme
- European Union [813091]
- Fondation ARC predoctoral fellowship
- INCa [PLBIO-2015-114]
- Agence Nationale de la Recherche (ANR) [ANR-17-CE15-0023] Funding Source: Agence Nationale de la Recherche (ANR)
- Marie Curie Actions (MSCA) [813091] Funding Source: Marie Curie Actions (MSCA)
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The transcription factor Helios plays a crucial role in suppressing the megakaryocyte lineage and maintaining pluripotency of hematopoietic stem cells in mice. Its absence leads to bias towards megakaryocyte lineage and partial resemblance to cells of aging animals, indicating the importance of negative and positive priming events in lineage commitment.
Our understanding of cell fate decisions in hematopoietic stem cells is incomplete. Here, we show that the transcription factor Helios is highly expressed in murine hematopoietic stem and progenitor cells (HSPCs), where it is required to suppress the separation of the platelet/megakaryocyte lineage from the HSPC pool. Helios acts mainly in quiescent cells, where it directly represses the megakaryocyte gene expression program in cells as early as the stem cell stage. Helios binding promotes chromatin compaction, notably at the regulatory regions of platelet-specific genes recognized by the Gata2 and Runx1 transcriptional activators, implicated in megakaryocyte priming. Helios null HSPCs are biased toward the megakaryocyte lineage at the expense of the lymphoid and partially resemble cells of aging animals. We propose that Helios acts as a guardian of HSPC pluripotency by continuously repressing the megakaryocyte fate, which in turn allows downstream lymphoid priming to take place. These results highlight the importance of negative and positive priming events in lineage commitment.
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