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

被引:56
作者
Cellot, Sonia [1 ,2 ,3 ]
Hope, Kristin J. [1 ]
Chagraoui, Jalila [1 ]
Sauvageau, Martin [1 ]
Deneault, Eric [1 ]
MacRae, Tara [1 ]
Mayotte, Nadine [1 ]
Wilhelm, Brian T. [1 ]
Landry, Josette R. [1 ]
Ting, Stephen B. [1 ,9 ]
Krosl, Jana [1 ]
Humphries, Keith [4 ,5 ]
Thompson, Alexander [6 ]
Sauvageau, Guy [1 ,2 ,7 ,8 ]
机构
[1] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada
[2] Univ Montreal, Fac Med, Montreal, PQ H3C 3J7, Canada
[3] Ste Justine Hosp, Div Hematol, Montreal, PQ, Canada
[4] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada
[5] Univ British Columbia, Dept Med, Vancouver, BC, Canada
[6] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast BT7 1NN, Antrim, North Ireland
[7] Hop Maison Neuve Rosemont, Div Hematol, Montreal, PQ H1T 2M4, Canada
[8] Hop Maison Neuve Rosemont, Leukemia Cell Bank Quebec, Montreal, PQ H1T 2M4, Canada
[9] Monash Univ, Melbourne, Vic 3004, Australia
基金
英国医学研究理事会;
关键词
HEMATOPOIETIC STEM-CELLS; OXIDATIVE DEMETHYLATION; SELF-RENEWAL; IN-VITRO; PROLIFERATION; POLYCOMB; GENES; CONTRIBUTES; REPRESSION; LEVEL;
D O I
10.1182/blood-2013-04-496281
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:1545 / 1555
页数:11
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