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...

Full description

Bibliographic Details
Main Authors: 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
Format: Article
Language:English
Published: Elsevier 2019-01-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124719300324
_version_ 1817992098603859968
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
work_keys_str_mv AT katharinameyer restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease
AT heathermfeldman restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease
AT taolu restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease
AT derekdrake restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease
AT elainetlim restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease
AT kinghwaling restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease
AT nicholasabishop restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease
AT yingpan restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease
AT jinsooseo restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease
AT yuantalin restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease
AT susancsu restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease
AT georgemchurch restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease
AT lihueitsai restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease
AT bruceayankner restandneuralgenenetworkdysregulationinipscmodelsofalzheimersdisease