Whole genome deconvolution unveils Alzheimer’s resilient epigenetic signature

Eloise Berson (), Anjali Sreenivas, Thanaphong Phongpreecha, Amalia Perna, Fiorella C. Grandi, Lei Xue, Neal G. Ravindra, Neelufar Payrovnaziri, Samson Mataraso, Yeasul Kim, Camilo Espinosa, Alan L. Chang, Martin Becker, Kathleen S. Montine, Edward J. Fox, Howard Y. Chang, M. Ryan Corces, Nima Aghaeepour and Thomas J. Montine
Additional contact information
Eloise Berson: Stanford University
Anjali Sreenivas: Stanford University
Thanaphong Phongpreecha: Stanford University
Amalia Perna: Stanford University
Fiorella C. Grandi: Gladstone Institute of Neurological Disease
Lei Xue: Stanford University
Neal G. Ravindra: Stanford University
Neelufar Payrovnaziri: Stanford University
Samson Mataraso: Stanford University
Yeasul Kim: Stanford University
Camilo Espinosa: Stanford University
Alan L. Chang: Stanford University
Martin Becker: Stanford University
Kathleen S. Montine: Stanford University
Edward J. Fox: Stanford University
Howard Y. Chang: Stanford University School of Medicine
M. Ryan Corces: Gladstone Institute of Neurological Disease
Nima Aghaeepour: Stanford University
Thomas J. Montine: Stanford University

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Assay for Transposase Accessible Chromatin by sequencing (ATAC-seq) accurately depicts the chromatin regulatory state and altered mechanisms guiding gene expression in disease. However, bulk sequencing entangles information from different cell types and obscures cellular heterogeneity. To address this, we developed Cellformer, a deep learning method that deconvolutes bulk ATAC-seq into cell type-specific expression across the whole genome. Cellformer enables cost-effective cell type-specific open chromatin profiling in large cohorts. Applied to 191 bulk samples from 3 brain regions, Cellformer identifies cell type-specific gene regulatory mechanisms involved in resilience to Alzheimer’s disease, an uncommon group of cognitively healthy individuals that harbor a high pathological load of Alzheimer’s disease. Cell type-resolved chromatin profiling unveils cell type-specific pathways and nominates potential epigenetic mediators underlying resilience that may illuminate therapeutic opportunities to limit the cognitive impact of the disease. Cellformer is freely available to facilitate future investigations using high-throughput bulk ATAC-seq data.

Date: 2023
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DOI: 10.1038/s41467-023-40611-4

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