Comparative RNAi Screens in Isogenic Human Stem Cells Reveal SMARCA4 as a Differential Regulator.
Animals
Cell Differentiation
/ genetics
Cell Self Renewal
/ genetics
Cells, Cultured
DNA Helicases
/ genetics
Hematopoietic Stem Cells
/ cytology
High-Throughput Screening Assays
/ methods
Humans
Induced Pluripotent Stem Cells
/ cytology
Mice
Neural Stem Cells
/ cytology
Nuclear Proteins
/ genetics
RNA Interference
Stem Cell Transplantation
/ methods
Stem Cells
/ cytology
Transcription Factors
/ genetics
RNAi
SMARCA4
SWI/SNF
comparative functional profiling
hematopoiesis
isogenic
neural differentiation
self-renewal
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
14 05 2019
14 05 2019
Historique:
received:
04
12
2018
revised:
26
03
2019
accepted:
27
03
2019
pubmed:
30
4
2019
medline:
28
4
2020
entrez:
30
4
2019
Statut:
ppublish
Résumé
Large-scale RNAi screens are a powerful approach to identify functions of genes in a cell-type-specific manner. For model organisms, genetically identical (isogenic) cells from different cell types are readily available, making comparative studies meaningful. However, large-scale screens in isogenic human primary cells remain challenging. Here, we show that RNAi screens are possible in genetically identical human stem cells, using induced pluripotent stem cells as intermediates. The screens revealed SMARCA4 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4) as a stemness regulator, while balancing differentiation distinctively for each cell type. SMARCA4 knockdown in hematopoietic stem and progenitor cells caused impaired self-renewal in vitro and in vivo with skewed myeloid differentiation; whereas, in neural stem cells, it impaired self-renewal while biasing differentiation toward neural lineage, through combinatorial SWI/SNF subunit assembly. Our findings pose a powerful approach for deciphering human stem cell biology and attribute distinct roles to SMARCA4 in stem cell maintenance.
Identifiants
pubmed: 31031192
pii: S2213-6711(19)30097-9
doi: 10.1016/j.stemcr.2019.03.012
pmc: PMC6523874
pii:
doi:
Substances chimiques
Nuclear Proteins
0
Transcription Factors
0
SMARCA4 protein, human
EC 3.6.1.-
DNA Helicases
EC 3.6.4.-
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1084-1098Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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