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

doi:10.1182/blood-2013-04-496281

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 language	English
Pages (from-to)	1545-1555
Number of pages	11
Journal	Blood
Volume	122
Issue number	9
Early online date	18 Jun 2013
DOIs	https://doi.org/10.1182/blood-2013-04-496281
Publication status	Published - 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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RNAi screen identifies Jarid1b as a major regulator of mouse HSC activityAccepted author manuscript, 839 KB

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title = "RNAi screen identifies Jarid1b as a major regulator of mouse HSC activity",

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{\textquoteright} 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.",

keywords = "RNAi screen, Jarid1b, HSC activity, HOX",

author = "Sonia Cellot and Hope, {Kirstin J.} and Jalila Chagraoui and Martin Sauvageau and {\'E}ric Deneault and Tara MacRae and Nadine Mayotte and Wilhelm, {Brian T.} and Landry, {Josette R.} and Ting, {Stephen B.} and Jana Krosl and Keith Humphries and Alexander Thompson and Guy Sauvageau",

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

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doi = "10.1182/blood-2013-04-496281",

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T1 - RNAi screen identifies Jarid1b as a major regulator of mouse HSC activity

AU - Cellot, Sonia

AU - Hope, Kirstin J.

AU - Chagraoui, Jalila

AU - Sauvageau, Martin

AU - Deneault, Éric

AU - MacRae, Tara

AU - Mayotte, Nadine

AU - Wilhelm, Brian T.

AU - Landry, Josette R.

AU - Ting, Stephen B.

AU - Krosl, Jana

AU - Humphries, Keith

AU - Thompson, Alexander

AU - Sauvageau, Guy

N1 - Manuscript published as the Plenary Paper in Blood, August 29, 2013; 122 (9) and introduced as the premier Inside Blood article.

PY - 2013/8/29

Y1 - 2013/8/29

N2 - 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.

AB - 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.

KW - RNAi screen

KW - Jarid1b

KW - HSC activity

KW - HOX

U2 - 10.1182/blood-2013-04-496281

DO - 10.1182/blood-2013-04-496281

M3 - Article

SN - 0006-4971

VL - 122

SP - 1545

EP - 1555

JO - Blood

JF - Blood

IS - 9

ER -

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

Abstract

Bibliographical note

Keywords

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