REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease
Summary: The molecular basis of the earliest neuronal changes that lead to Alzheimer’s disease (AD) is unclear. Here, we analyze neural cells derived from sporadic AD (SAD), APOE4 gene-edited and control induced pluripotent stem cells (iPSCs). We observe major differences in iPSC-derived neural prog...
Main Authors: | , , , , , , , , , , , , , |
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Format: | Article |
Language: | English |
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Elsevier
2019-01-01
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Series: | Cell Reports |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719300324 |
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author | Katharina Meyer Heather M. Feldman Tao Lu Derek Drake Elaine T. Lim King-Hwa Ling Nicholas A. Bishop Ying Pan Jinsoo Seo Yuan-Ta Lin Susan C. Su George M. Church Li-Huei Tsai Bruce A. Yankner |
author_facet | Katharina Meyer Heather M. Feldman Tao Lu Derek Drake Elaine T. Lim King-Hwa Ling Nicholas A. Bishop Ying Pan Jinsoo Seo Yuan-Ta Lin Susan C. Su George M. Church Li-Huei Tsai Bruce A. Yankner |
author_sort | Katharina Meyer |
collection | DOAJ |
description | Summary: The molecular basis of the earliest neuronal changes that lead to Alzheimer’s disease (AD) is unclear. Here, we analyze neural cells derived from sporadic AD (SAD), APOE4 gene-edited and control induced pluripotent stem cells (iPSCs). We observe major differences in iPSC-derived neural progenitor (NP) cells and neurons in gene networks related to neuronal differentiation, neurogenesis, and synaptic transmission. The iPSC-derived neural cells from SAD patients exhibit accelerated neural differentiation and reduced progenitor cell renewal. Moreover, a similar phenotype appears in NP cells and cerebral organoids derived from APOE4 iPSCs. Impaired function of the transcriptional repressor REST is strongly implicated in the altered transcriptome and differentiation state. SAD and APOE4 expression result in reduced REST nuclear translocation and chromatin binding, and disruption of the nuclear lamina. Thus, dysregulation of neural gene networks may set in motion the pathologic cascade that leads to AD. : Meyer et al. derive neural progenitors, neurons, and cerebral organoids from sporadic Alzheimer’s disease (SAD) and APOE4 gene-edited iPSCs. SAD and APOE4 expression alter the neural transcriptome and differentiation in part through loss of function of the transcriptional repressor REST. Thus, neural gene network dysregulation may lead to Alzheimer’s disease. Keywords: neural progenitor, induced pluripotent stem cell, Alzheimer’s disease, apolipoprotein E, neural differentiation, neurogenesis, REST, polycomb, epigenetic, organoid |
first_indexed | 2024-04-14T01:21:55Z |
format | Article |
id | doaj.art-badcc8e4bd05429e89f06087a8cb13bb |
institution | Directory Open Access Journal |
issn | 2211-1247 |
language | English |
last_indexed | 2024-04-14T01:21:55Z |
publishDate | 2019-01-01 |
publisher | Elsevier |
record_format | Article |
series | Cell Reports |
spelling | doaj.art-badcc8e4bd05429e89f06087a8cb13bb2022-12-22T02:20:37ZengElsevierCell Reports2211-12472019-01-0126511121127.e9REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s DiseaseKatharina Meyer0Heather M. Feldman1Tao Lu2Derek Drake3Elaine T. Lim4King-Hwa Ling5Nicholas A. Bishop6Ying Pan7Jinsoo Seo8Yuan-Ta Lin9Susan C. Su10George M. Church11Li-Huei Tsai12Bruce A. Yankner13Department of Genetics, Harvard Medical School, Boston, MA 02115, USADepartment of Genetics, Harvard Medical School, Boston, MA 02115, USADepartment of Genetics, Harvard Medical School, Boston, MA 02115, USADepartment of Genetics, Harvard Medical School, Boston, MA 02115, USADepartment of Genetics, Harvard Medical School, Boston, MA 02115, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USADepartment of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, MalaysiaDepartment of Genetics, Harvard Medical School, Boston, MA 02115, USADepartment of Genetics, Harvard Medical School, Boston, MA 02115, USAThe Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USAThe Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USAThe Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USADepartment of Genetics, Harvard Medical School, Boston, MA 02115, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USAThe Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USADepartment of Genetics, Harvard Medical School, Boston, MA 02115, USA; Corresponding authorSummary: The molecular basis of the earliest neuronal changes that lead to Alzheimer’s disease (AD) is unclear. Here, we analyze neural cells derived from sporadic AD (SAD), APOE4 gene-edited and control induced pluripotent stem cells (iPSCs). We observe major differences in iPSC-derived neural progenitor (NP) cells and neurons in gene networks related to neuronal differentiation, neurogenesis, and synaptic transmission. The iPSC-derived neural cells from SAD patients exhibit accelerated neural differentiation and reduced progenitor cell renewal. Moreover, a similar phenotype appears in NP cells and cerebral organoids derived from APOE4 iPSCs. Impaired function of the transcriptional repressor REST is strongly implicated in the altered transcriptome and differentiation state. SAD and APOE4 expression result in reduced REST nuclear translocation and chromatin binding, and disruption of the nuclear lamina. Thus, dysregulation of neural gene networks may set in motion the pathologic cascade that leads to AD. : Meyer et al. derive neural progenitors, neurons, and cerebral organoids from sporadic Alzheimer’s disease (SAD) and APOE4 gene-edited iPSCs. SAD and APOE4 expression alter the neural transcriptome and differentiation in part through loss of function of the transcriptional repressor REST. Thus, neural gene network dysregulation may lead to Alzheimer’s disease. Keywords: neural progenitor, induced pluripotent stem cell, Alzheimer’s disease, apolipoprotein E, neural differentiation, neurogenesis, REST, polycomb, epigenetic, organoidhttp://www.sciencedirect.com/science/article/pii/S2211124719300324 |
spellingShingle | Katharina Meyer Heather M. Feldman Tao Lu Derek Drake Elaine T. Lim King-Hwa Ling Nicholas A. Bishop Ying Pan Jinsoo Seo Yuan-Ta Lin Susan C. Su George M. Church Li-Huei Tsai Bruce A. Yankner REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease Cell Reports |
title | REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease |
title_full | REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease |
title_fullStr | REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease |
title_full_unstemmed | REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease |
title_short | REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease |
title_sort | rest and neural gene network dysregulation in ipsc models of alzheimer s disease |
url | http://www.sciencedirect.com/science/article/pii/S2211124719300324 |
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