title: Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs.
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, 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.
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden.
authors.forename: Roman
authors.initials: R
authors.lastname: Galeev
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Baudet
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden.
authors.forename: Praveen
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Division of Molecular Hematology, Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rundberg Nilsson
authors.affiliation: Division of Hematology and Transfusion Medicine, Lund University, 221 84 Lund, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Nilsson
authors.affiliation: Division of Molecular Hematology, Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden.
authors.forename: Shamit
authors.initials: S
authors.lastname: Soneji
authors.affiliation: Division of Oncology and Pathology, Lund University, 223 63 Lund, Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Törngren
authors.affiliation: Division of Oncology and Pathology, Lund University, 223 63 Lund, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.affiliation: Division of Oncology and Pathology, Lund University, 223 63 Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Kvist
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden. Electronic address: jonas.larsson@med.lu.se.
authors.forename: Jonas
authors.initials: J
authors.lastname: Larsson
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology; D020869:Gene Expression Profiling; D015894:Genome, Human; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014183:Transplantation, Heterologous; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D034741:RNA, Small Interfering; D000097722:Cohesins