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Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs

Galeev, Roman LU ; Baudet, Aurélie LU ; Kumar, Praveen; Rundberg Nilsson, Alexandra LU ; Nilsson, Björn LU ; Soneji, Shamit LU ; Törngren, Therese LU ; Borg, Åke LU ; Kvist, Anders LU and Larsson, Jonas LU (2016) In Cell Reports 14(12). p.2988-3000
Abstract

To gain insights into the regulatory mechanisms of hematopoietic stem cells (HSCs), we employed a genome-wide RNAi screen in human cord-blood derived cells and identified candidate genes whose knockdown maintained the HSC phenotype during culture. A striking finding was the identification of members of the cohesin complex (STAG2, RAD21, STAG1, and SMC3) among the top 20 genes from the screen. Upon individual validation of these cohesin genes, we found that their knockdown led to an immediate expansion of cells with an HSC phenotype in vitro. A similar expansion was observed in vivo following transplantation to immunodeficient mice. Transcriptome analysis of cohesin-deficient CD34(+) cells showed an upregulation of HSC-specific genes,... (More)

To gain insights into the regulatory mechanisms of hematopoietic stem cells (HSCs), we employed a genome-wide RNAi screen in human cord-blood derived cells and identified candidate genes whose knockdown maintained the HSC phenotype during culture. A striking finding was the identification of members of the cohesin complex (STAG2, RAD21, STAG1, and SMC3) among the top 20 genes from the screen. Upon individual validation of these cohesin genes, we found that their knockdown led to an immediate expansion of cells with an HSC phenotype in vitro. A similar expansion was observed in vivo following transplantation to immunodeficient mice. Transcriptome analysis of cohesin-deficient CD34(+) cells showed an upregulation of HSC-specific genes, demonstrating an immediate shift toward a more stem-cell-like gene expression signature upon cohesin deficiency. Our findings implicate cohesin as a major regulator of HSCs and illustrate the power of global RNAi screens to identify modifiers of cell fate.

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author
organization
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type
Contribution to journal
publication status
published
subject
in
Cell Reports
volume
14
issue
12
pages
13 pages
publisher
Cell Press
external identifiers
  • Scopus:84961223488
  • WOS:000372869300019
ISSN
2211-1247
DOI
10.1016/j.celrep.2016.02.082
language
English
LU publication?
yes
id
1aa3f692-881f-403c-8aa2-44dbdf8963ce
date added to LUP
2016-04-13 15:11:09
date last changed
2016-10-13 05:06:12
@misc{1aa3f692-881f-403c-8aa2-44dbdf8963ce,
  abstract     = {<p>To gain insights into the regulatory mechanisms of hematopoietic stem cells (HSCs), we employed a genome-wide RNAi screen in human cord-blood derived cells and identified candidate genes whose knockdown maintained the HSC phenotype during culture. A striking finding was the identification of members of the cohesin complex (STAG2, RAD21, STAG1, and SMC3) among the top 20 genes from the screen. Upon individual validation of these cohesin genes, we found that their knockdown led to an immediate expansion of cells with an HSC phenotype in vitro. A similar expansion was observed in vivo following transplantation to immunodeficient mice. Transcriptome analysis of cohesin-deficient CD34(+) cells showed an upregulation of HSC-specific genes, demonstrating an immediate shift toward a more stem-cell-like gene expression signature upon cohesin deficiency. Our findings implicate cohesin as a major regulator of HSCs and illustrate the power of global RNAi screens to identify modifiers of cell fate.</p>},
  author       = {Galeev, Roman and Baudet, Aurélie and Kumar, Praveen and Rundberg Nilsson, Alexandra and Nilsson, Björn and Soneji, Shamit and Törngren, Therese and Borg, Åke and Kvist, Anders and Larsson, Jonas},
  issn         = {2211-1247},
  language     = {eng},
  number       = {12},
  pages        = {2988--3000},
  publisher    = {ARRAY(0x8e92398)},
  series       = {Cell Reports},
  title        = {Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs},
  url          = {http://dx.doi.org/10.1016/j.celrep.2016.02.082},
  volume       = {14},
  year         = {2016},
}