RNAi Screen Identifies Jarid1b As a Major Regulator of Mouse HSC Activity

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2013 Jun 20

PMID 23777767

Citations 36

Authors

Sonia Cellot

Kristin J Hope

Jalila Chagraoui

Martin Sauvageau

Eric Deneault

Tara MacRae

Nadine Mayotte

Brian T Wilhelm

Josette R Landry

Stephen B Ting

Jana Krosl

Keith Humphries

Alexander Thompson

Guy Sauvageau

Affiliations

Soon will be listed here.

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 that target mono-, di-, and trimethylated lysine residues of histone (or nonhistone) proteins. To evaluate their role in regulation of hematopoietic stem cell (HSC) behavior, we performed an in vivo RNAi-based functional screen and demonstrated that Jarid1b and Jhdm1f play opposing roles in regulation of HSC activity. Decrease in Jarid1b levels correlated with an in vitro expansion of HSCs with preserved long-term in vivo lymphomyeloid differentiation potential. Through RNA sequencing analysis, Jarid1b knockdown was associated with increased expression levels of several HSC regulators (Hoxa7, Hoxa9, Hoxa10, Hes1, Gata2) and reduced levels of differentiation-associated genes. shRNA against Jhdmlf, in contrast, impaired hematopoietic reconstitution of bone marrow cells. Together, our studies identified Jarid1b as a negative regulator of HSC activity and Jhdmlf as a positive regulator of HSC activity.

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