Evidence map›Paper›PMID 33663567›Full record

ArticleGenome biology2021

Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity.

Matan Sorek, Walaa Oweis, Malka Nissim-Rafinia, Moria Maman, Shahar Simon, Cynthia C Hession, Xian Adiconis, Sean K Simmons, Neville E Sanjana, Xi Shi and 8 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Genome biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
0.8field-weighted citation impact, top 30% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed, 14 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 5 institutions in 5 countries.

Matan SorekDepartment of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel.
Walaa OweisDepartment of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel.
Malka Nissim-RafiniaDepartment of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel.
Moria MamanDepartment of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel.
Shahar SimonDepartment of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel.
Cynthia C HessionStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Xian AdiconisStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Sean K SimmonsStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Neville E SanjanaBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Xi ShiBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Congyi LuNew York Genome Center and Department of Biology, New York University, New York, NY, USA.
Jen Q PanStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Xiaohong XuDepartment of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, 613 Huangpu Avenue West, Guangzhou, 510632, Guangdong, China.
Mahmoud A PouladiTranslational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore, 138648, Singapore.
Lisa M EllerbyBuck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94945, USA.
Feng ZhangBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Joshua Z LevinStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Eran MeshorerDepartment of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel. eran.meshorer@mail.huji.ac.il.ORCID 0000-0003-4777-986X
Broad Institute · USHebrew University of Jerusalem · ILAgency for Science, Technology and Research · SGBuck Institute for Research on Aging · USNew York Genome Center · US

Funding

Programmable RNA-targeting toolsR01HG009761 · NHGRI · BROAD INSTITUTE, INC. · PI ZHANG, FENG · 2017 to 2024
$7.5M
Exploration of Diverse Mobile Genetic Elements for Precision Genome ManipulationDP1HL141201 · NHLBI · BROAD INSTITUTE, INC. · PI ZHANG, FENG · 2017 to 2021
$6.2M
Identifying Factors Regulating Medium Spiny Neuron Differentiation or Maintenance as Therapeutic Targets for Huntington's Disease using Induced Pluripotent Stem CellsR01NS100529 · NINDS · BUCK INSTITUTE FOR RESEARCH ON AGING · PI Lisa M Ellerby · 2016 to 2026
$5.6M
Massively-parallel functional interrogation of psychiatric geneticsR01MH110049 · NIMH · BROAD INSTITUTE, INC. · PI ZHANG, FENG · 2015 to 2019
$5.5M
Predicting the functional impact of non-coding mutations using patient-specific gene regulatory networksR01CA218668 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI EKTA KHURANA, Neville Sanjana · 2018 to 2026
$4.7M
In situ functional genomics to understand transcriptional regulationDP2HG010099 · NHGRI · NEW YORK GENOME CENTER · PI SANJANA, NEVILLE · 2017 to 2022
$4.4M
High-Throughput Screens for CaV3.3 Selective T-type Calcium Channel ModulatorsR01MH115045 · NIMH · BROAD INSTITUTE, INC. · PI COTTRELL, JEFFREY RICHARD, PAN, JEN QIAN · 2018 to 2020
$2.3M
Genetic Correction of Mutant Huntingtin in VivoR01NS094422 · NINDS · BUCK INSTITUTE FOR RESEARCH ON AGING · PI ELLERBY, LISA M · 2016 to 2020
$2.1M
Genome engineering tools for functional screening of non-coding elementsR00HG008171 · NHGRI · NEW YORK GENOME CENTER · PI SANJANA, NEVILLE · 2016 to 2018
$733k
Howard Hughes Medical InstituteNCI NIH HHS R01 CA218668NCI NIH HHS R01CA218668NHGRI NIH HHS DP2 HG010099NHGRI NIH HHS R00 HG008171NHGRI NIH HHS R01 HG009761NHLBI NIH HHS DP1 HL141201NIH HHS DP2HG010099NIH HHS HG009761NIH HHS MH110049NIH HHS NS094422NIH HHS R00HG008171NIH HHS R01NS100529NIMH NIH HHS R01 MH110049NIMH NIH HHS R01 MH115045NINDS NIH HHS R01 NS094422NINDS NIH HHS R01 NS100529
6 · The paper itself

Abstract

backgroundMany 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.

resultsAnalyzing 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.

conclusionsOverall, 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.

Indexed as

Gene Expression RegulationGenetic HeterogeneityGenetic Predisposition to DiseaseModels, BiologicalAdultGene Expression ProfilingGene Regulatory NetworksGenetic BackgroundHigh-Throughput Nucleotide SequencingHumansMutationNeurodegenerative DiseasesPluripotent Stem CellsRNA-SeqSingle-Cell AnalysisHuntington’s diseaseNeurodegenerative diseasesNeurological diseasesPluripotent stem cellsscRNA-seqSingle cellSmart-seq2Stem cell modelTranscriptional heterogeneity

Identifiers

PMID33663567
PMCPMC7934477
OpenAlexW3135158970

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.