Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity.
Adult
Gene Expression Profiling
Gene Expression Regulation
Gene Regulatory Networks
Genetic Background
Genetic Heterogeneity
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
Humans
Models, Biological
Mutation
Neurodegenerative Diseases
/ etiology
Pluripotent Stem Cells
/ metabolism
RNA-Seq
Single-Cell Analysis
/ methods
Huntington’s disease
Neurodegenerative diseases
Neurological diseases
Pluripotent stem cells
Single cell
Smart-seq2
Stem cell model
Transcriptional heterogeneity
scRNA-seq
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
04 03 2021
04 03 2021
Historique:
received:
16
04
2020
accepted:
18
02
2021
entrez:
5
3
2021
pubmed:
6
3
2021
medline:
13
1
2022
Statut:
epublish
Résumé
Many neurodegenerative diseases develop only later in life, when cells in the nervous system lose their structure or function. In many forms of neurodegenerative diseases, this late-onset phenomenon remains largely unexplained. Analyzing single-cell RNA sequencing from Alzheimer's disease (AD) and Huntington's disease (HD) patients, we find increased transcriptional heterogeneity in disease-state neurons. We hypothesize that transcriptional heterogeneity precedes neurodegenerative disease pathologies. To test this idea experimentally, we use juvenile forms (72Q; 180Q) of HD iPSCs, differentiate them into committed neuronal progenitors, and obtain single-cell expression profiles. We show a global increase in gene expression variability in HD. Autophagy genes become more stable, while energy and actin-related genes become more variable in the mutant cells. Knocking down several differentially variable genes results in increased aggregate formation, a pathology associated with HD. We further validate the increased transcriptional heterogeneity in CHD8+/- cells, a model for autism spectrum disorder. Overall, our results suggest that although neurodegenerative diseases develop over time, transcriptional regulation imbalance is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value.
Sections du résumé
BACKGROUND
Many neurodegenerative diseases develop only later in life, when cells in the nervous system lose their structure or function. In many forms of neurodegenerative diseases, this late-onset phenomenon remains largely unexplained.
RESULTS
Analyzing single-cell RNA sequencing from Alzheimer's disease (AD) and Huntington's disease (HD) patients, we find increased transcriptional heterogeneity in disease-state neurons. We hypothesize that transcriptional heterogeneity precedes neurodegenerative disease pathologies. To test this idea experimentally, we use juvenile forms (72Q; 180Q) of HD iPSCs, differentiate them into committed neuronal progenitors, and obtain single-cell expression profiles. We show a global increase in gene expression variability in HD. Autophagy genes become more stable, while energy and actin-related genes become more variable in the mutant cells. Knocking down several differentially variable genes results in increased aggregate formation, a pathology associated with HD. We further validate the increased transcriptional heterogeneity in CHD8+/- cells, a model for autism spectrum disorder.
CONCLUSIONS
Overall, our results suggest that although neurodegenerative diseases develop over time, transcriptional regulation imbalance is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value.
Identifiants
pubmed: 33663567
doi: 10.1186/s13059-021-02301-6
pii: 10.1186/s13059-021-02301-6
pmc: PMC7934477
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
73Subventions
Organisme : National Institutes of Health (US)
ID : HL141201
Organisme : NIH HHS
ID : HG009761
Pays : United States
Organisme : NIH HHS
ID : R00HG008171
Pays : United States
Organisme : NIH HHS
ID : MH110049
Pays : United States
Organisme : NCI NIH HHS
ID : R01CA218668
Pays : United States
Organisme : NIH HHS
ID : R01NS100529
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIH HHS
ID : NS094422
Pays : United States
Organisme : NIH HHS
ID : DP2HG010099
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH115045
Pays : United States
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