Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity.
Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity.
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DOI：
10.1186/s13059-021-02301-6
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发表时间：
2021-03-04
期刊：
影响因子：
12.3
通讯作者：
Meshorer E
中科院分区：
文献类型：
--
作者：
Sorek M;Oweis W;Nissim-Rafinia M;Maman M;Simon S;Hession CC;Adiconis X;Simmons SK;Sanjana NE;Shi X;Lu C;Pan JQ;Xu X;Pouladi MA;Ellerby LM;Zhang F;Levin JZ;Meshorer E
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. The online version contains supplementary material available at 10.1186/s13059-021-02301-6.
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影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
DOI：
10.3233/jad-179939
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Bennett DA;Buchman AS;Boyle PA;Barnes LL;Wilson RS;Schneider JA
通讯作者：
Schneider JA
影响因子：
64.5
作者：
Ji, Ni;Middelkoop, Teije C.;van Oudenaarden, Alexander
通讯作者：
van Oudenaarden, Alexander
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
23.9
作者：
通讯作者：
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