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Epigenomic dissection of Alzheimer's disease pinpoints causal variants and reveals epigenome erosion.
Xiong, Xushen; James, Benjamin T; Boix, Carles A; Park, Yongjin P; Galani, Kyriaki; Victor, Matheus B; Sun, Na; Hou, Lei; Ho, Li-Lun; Mantero, Julio; Scannail, Aine Ni; Dileep, Vishnu; Dong, Weixiu; Mathys, Hansruedi; Bennett, David A; Tsai, Li-Huei; Kellis, Manolis.
Afiliación
  • Xiong X; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China.
  • James BT; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
  • Boix CA; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
  • Park YP; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Pathology and Laboratory Medicine, Department of Statistics, University of
  • Galani K; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
  • Victor MB; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Sun N; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
  • Hou L; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
  • Ho LL; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
  • Mantero J; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
  • Scannail AN; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Dileep V; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Dong W; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
  • Mathys H; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • Bennett DA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
  • Tsai LH; The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: lhtsai@mit.edu.
  • Kellis M; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA. Electronic address: manoli@mit.edu.
Cell ; 186(20): 4422-4437.e21, 2023 09 28.
Article en En | MEDLINE | ID: mdl-37774680
Recent work has identified dozens of non-coding loci for Alzheimer's disease (AD) risk, but their mechanisms and AD transcriptional regulatory circuitry are poorly understood. Here, we profile epigenomic and transcriptomic landscapes of 850,000 nuclei from prefrontal cortexes of 92 individuals with and without AD to build a map of the brain regulome, including epigenomic profiles, transcriptional regulators, co-accessibility modules, and peak-to-gene links in a cell-type-specific manner. We develop methods for multimodal integration and detecting regulatory modules using peak-to-gene linking. We show AD risk loci are enriched in microglial enhancers and for specific TFs including SPI1, ELF2, and RUNX1. We detect 9,628 cell-type-specific ATAC-QTL loci, which we integrate alongside peak-to-gene links to prioritize AD variant regulatory circuits. We report differential accessibility of regulatory modules in late AD in glia and in early AD in neurons. Strikingly, late-stage AD brains show global epigenome dysregulation indicative of epigenome erosion and cell identity loss.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Encéfalo / Regulación de la Expresión Génica / Enfermedad de Alzheimer Límite: Humans Idioma: En Revista: Cell Año: 2023 Tipo del documento: Article País de afiliación: China
Texto completo
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Encéfalo / Regulación de la Expresión Génica / Enfermedad de Alzheimer Límite: Humans Idioma: En Revista: Cell Año: 2023 Tipo del documento: Article País de afiliación: China