RNAi screen identifies Jarid1b as a major regulator of mouse HSC activity

Sonia Cellot, Kirstin J. Hope, Jalila Chagraoui, Martin Sauvageau, Éric Deneault, Tara MacRae, Nadine Mayotte, Brian T. Wilhelm, Josette R. Landry, Stephen B. Ting, Jana Krosl, Keith Humphries, Alexander Thompson, Guy Sauvageau

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Abstract

Histone methylation is a dynamic and reversible process proposed to directly impact on stem cell fate. The Jumonji (JmjC) domain-containing family of demethylases comprises 27 members which can demethylate mono-, di- and tri-methylated lysine residues of histone (or non-histone) targets. To evaluate their role in regulation of hematopoietic stem cell (HSC) behaviour we performed a RNAi-based screen and found that demethylases JARID1B (H3K4) and JHDM1F (H3K9) play opposing roles in regulation of HSC activity. Decrease in Jarid1b levels correlated with an in vitro expansion of HSC with preserved long term in vivo lympho-myeloid differentiation potential. Jarid1b knockdown was associated with an increase in expression levels of 5’ Hoxa cluster genes and CxCl5 , and reduced levels of Pu.1, Egr1 and Cav1. shRNA against Jhdmlf, in contrast, impaired hematopoietic reconstitution of bone marrow cells. Together, our studies identified Jarid1b as a negative, and Jhdmlf as a positive regulator of HSC activity.
Original languageEnglish
Pages (from-to)1545-1555
Number of pages11
JournalBlood
Volume122
Issue number9
Early online date18 Jun 2013
DOIs
Publication statusPublished - 29 Aug 2013

Bibliographical note

Manuscript published as the Plenary Paper in Blood, August 29, 2013; 122 (9) and introduced as the premier Inside Blood article.

Keywords

  • RNAi screen
  • Jarid1b
  • HSC activity
  • HOX

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    Cellot, S., Hope, K. J., Chagraoui, J., Sauvageau, M., Deneault, É., MacRae, T., Mayotte, N., Wilhelm, B. T., Landry, J. R., Ting, S. B., Krosl, J., Humphries, K., Thompson, A., & Sauvageau, G. (2013). RNAi screen identifies Jarid1b as a major regulator of mouse HSC activity. Blood, 122(9), 1545-1555. https://doi.org/10.1182/blood-2013-04-496281