Robust enhancer-gene regulation identified by single-cell transcriptomes and epigenomes

Fangming Xie, Ethan J. Armand, Zizhen Yao, Hanqing Liu, Anna Bartlett, M. Margarita Behrens, Yang Eric Li, Jacinta D. Lucero, Chongyuan Luo, Joseph R. Nery, Antonio Pinto-Duarte, Olivier B. Poirion, Sebastian Preissl, Angeline C. Rivkin, Bosiljka Tasic, Hongkui Zeng, Bing Ren, Joseph R. Ecker, Eran A. Mukamel

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Single-cell sequencing could help to solve the fundamental challenge of linking millions of cell-type-specific enhancers with their target genes. However, this task is confounded by patterns of gene co-expression in much the same way that genetic correlation due to linkage disequilibrium confounds fine-mapping in genome-wide association studies (GWAS). We developed a non-parametric permutation-based procedure to establish stringent statistical criteria to control the risk of false-positive associations in enhancer-gene association studies (EGAS). We applied our procedure to large-scale transcriptome and epigenome data from multiple tissues and species, including the mouse and human brain, to predict enhancer-gene associations genome wide. We tested the functional validity of our predictions by comparing them with chromatin conformation data and causal enhancer perturbation experiments. Our study shows how controlling for gene co-expression enables robust enhancer-gene linkage using single-cell sequencing data.

Original languageEnglish
Article number100342
JournalCell Genomics
Volume3
Issue number7
DOIs
StatePublished - Jul 12 2023

Keywords

  • DNA methylation
  • brain
  • chromatin accessibility
  • enhancer
  • epigenome

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