Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs
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...
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doaj-ba32c2d6ac454633a0b25ed4e8f1173a2020-11-25T01:39:04ZengElsevierCell Reports2211-12472016-03-0114122988300010.1016/j.celrep.2016.02.082Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCsRoman Galeev0Aurélie Baudet1Praveen Kumar2Alexandra Rundberg Nilsson3Björn Nilsson4Shamit Soneji5Therese Törngren6Åke Borg7Anders Kvist8Jonas Larsson9Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 221 84 Lund, SwedenDivision of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 221 84 Lund, SwedenDivision of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 221 84 Lund, SwedenDivision of Molecular Hematology, Lund Stem Cell Center, Lund University, 221 84 Lund, SwedenDivision of Hematology and Transfusion Medicine, Lund University, 221 84 Lund, SwedenDivision of Molecular Hematology, Lund Stem Cell Center, Lund University, 221 84 Lund, SwedenDivision of Oncology and Pathology, Lund University, 223 63 Lund, SwedenDivision of Oncology and Pathology, Lund University, 223 63 Lund, SwedenDivision of Oncology and Pathology, Lund University, 223 63 Lund, SwedenDivision of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 221 84 Lund, SwedenTo 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.http://www.sciencedirect.com/science/article/pii/S2211124716302170 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Roman Galeev Aurélie Baudet Praveen Kumar Alexandra Rundberg Nilsson Björn Nilsson Shamit Soneji Therese Törngren Åke Borg Anders Kvist Jonas Larsson |
spellingShingle |
Roman Galeev Aurélie Baudet Praveen Kumar Alexandra Rundberg Nilsson Björn Nilsson Shamit Soneji Therese Törngren Åke Borg Anders Kvist Jonas Larsson Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs Cell Reports |
author_facet |
Roman Galeev Aurélie Baudet Praveen Kumar Alexandra Rundberg Nilsson Björn Nilsson Shamit Soneji Therese Törngren Åke Borg Anders Kvist Jonas Larsson |
author_sort |
Roman Galeev |
title |
Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs |
title_short |
Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs |
title_full |
Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs |
title_fullStr |
Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs |
title_full_unstemmed |
Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs |
title_sort |
genome-wide rnai screen identifies cohesin genes as modifiers of renewal and differentiation in human hscs |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2016-03-01 |
description |
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. |
url |
http://www.sciencedirect.com/science/article/pii/S2211124716302170 |
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