Deep learning imputes DNA methylation states in single cells and enhances the detection of epigenetic alterations in schizophrenia.

Journal: Cell genomics
PMID: 39986279

Abstract

DNA methylation (DNAm) is a key epigenetic mark with essential roles in gene regulation, mammalian development, and human diseases. Single-cell technologies enable profiling DNAm at cytosines in individual cells, but they often suffer from low coverage for CpG sites. We introduce scMeFormer, a transformer-based deep learning model for imputing DNAm states at each CpG site in single cells. Comprehensive evaluations across five single-nucleus DNAm datasets from human and mouse demonstrate scMeFormer's superior performance over alternative models, achieving high-fidelity imputation even with coverage reduced to 10% of original CpG sites. Applying scMeFormer to a single-nucleus DNAm dataset from the prefrontal cortex of patients with schizophrenia and controls identified thousands of schizophrenia-associated differentially methylated regions that would have remained undetectable without imputation and added granularity to our understanding of epigenetic alterations in schizophrenia. We anticipate that scMeFormer will be a valuable tool for advancing single-cell DNAm studies.

Authors

  • Jiyun Zhou
  • Chongyuan Luo
    Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
  • Hanqing Liu
    Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing, 100081, China.
  • Matthew G Heffel
    Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Richard E Straub
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21287, USA.
  • Joel E Kleinman
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
  • Thomas M Hyde
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
  • Joseph R Ecker
    Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
  • Daniel R Weinberger
    Genes, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of HealthBethesda, MD, USA; The Lieber Institute for Brain DevelopmentBaltimore, MD, USA; Departments of Psychiatry, Neurology and Neuroscience, Johns Hopkins University School of MedicineBaltimore, MD, USA; The Institute of Genetic Medicine, Johns Hopkins University School of MedicineBaltimore, MD, USA.
  • Shizhong Han
    12 Sigma Technologies, San Diego, CA 92130, USA.

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