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

Genome Biology

Xi Shi¹  Feng Zhang²  Neville E. Sanjana³  Lisa M. Ellerby⁴  Malka Nissim-Rafinia⁵  Shahar Simon⁵  Walaa Oweis⁵  Moria Maman⁵  Matan Sorek⁶  Eran Meshorer⁶  Xiaohong Xu⁷  Congyi Lu⁸  Jen Q. Pan⁹  Xian Adiconis^1,10  Sean K. Simmons^1,10  Cynthia C. Hession^1,10  Joshua Z. Levin^1,10  Mahmoud A. Pouladi^1,11 

[1] Broad Institute of MIT and Harvard, Cambridge, MA, USA;Broad Institute of MIT and Harvard, Cambridge, MA, USA;McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA;Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA;Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA;Broad Institute of MIT and Harvard, Cambridge, MA, USA;McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA;New York Genome Center and Department of Biology, New York University, New York, NY, USA;Buck Institute for Research on Aging, 8001 Redwood Blvd, 94945, Novato, CA, USA;Department of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel;Department of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel;The Edmond and Lily Center for Brain Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel;Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, 613 Huangpu Avenue West, 510632, Guangzhou, Guangdong, China;Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, 138648, Singapore, Singapore;New York Genome Center and Department of Biology, New York University, New York, NY, USA;Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA;Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA;Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA;Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, 138648, Singapore, Singapore;Department of Physiology, National University of Singapore, 117597, Singapore, Singapore;British Columbia Children’s Hospital Research Institute, Department of Medical Genetics, University of British Columbia, V5Z 4H4, Vancouver, Canada;

关键词: Transcriptional heterogeneity;    Single cell;    scRNA-seq;    Neurological diseases;    Neurodegenerative diseases;    Huntington’s disease;    Pluripotent stem cells;    Stem cell model;    Smart-seq2;   

DOI  :  10.1186/s13059-021-02301-6

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY