Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs
(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.
(Less)
- author
- 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
- organization
-
- Division of Molecular Medicine and Gene Therapy
- Division of Molecular Hematology (DMH)
- Division of Hematology and Transfusion Medicine
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- Section V
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- publishing date
- 2016
- 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
- pmid:26997282
- 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
- 2024-09-07 08:46:51
@article{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 = {{Cell Press}}, 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}}, doi = {{10.1016/j.celrep.2016.02.082}}, volume = {{14}}, year = {{2016}}, }