REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease
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
Affiliations
Katharina Meyer
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Heather M. Feldman
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Tao Lu
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Derek Drake
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Elaine T. Lim
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
King-Hwa Ling
Department 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, Malaysia
Nicholas A. Bishop
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Ying Pan
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Jinsoo Seo
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Yuan-Ta Lin
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Susan C. Su
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
George M. Church
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
Li-Huei Tsai
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Bruce A. Yankner
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Corresponding author
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
