Integrated DNA Methylome and Transcriptome Signatures of Lung CD4+ T Cells in Sarcoidosis

Authors:
  • CMCamille Moore
    Camille Moore
  • SLShu-Yi Liao
    Shu-Yi Liao
  • LLLi Li
    Li Li
  • JCJonathan Cardwell
    Jonathan Cardwell
  • KMKristyn MacPhail
    Kristyn MacPhail
  • MMMargaret M. Mroz
    Margaret M. Mroz
  • CRChristina Riley
    Christina Riley
  • NLNancy W. Lin
    Nancy W. Lin
  • EDElizabeth Davidson
    Elizabeth Davidson
  • CRClara I. Restrepo
    Clara I. Restrepo
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Abstract
Rationale: Activated pulmonary CD4+ T lymphocytes are a critical part of sarcoidosis pathogenesis. Objectives: To identify molecular changes associated with sarcoidosis risk primarily and progression secondarily, we profiled and integrated DNA methylome and transcriptome data in lung CD4+ T cells. Methods: Bronchoalveolar lavage (BAL) CD4+ T cells were isolated from 29 sarcoidosis (16 progressive [SarcP] and 13 non-progressive [SarcNP]) cases and 19 healthy controls. mRNA was sequenced and DNA methylation profiled on Illumina HumanMethylationEPIC arrays. Linear models were fit to test for effect of diagnosis, adjusting for age and sex. Methylation models were adjusted for unknown batch effects, inflation and bias. We used Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) to integrate methylome and transcriptome datasets and validated targets using single cell RNA-seq. Measurements and Main Results: Using transcriptome-wide significance, differentially expressed (DE) transcripts were identified in sarcoidosis (39), SarcNP (23), and SarcP (7) compared to controls. Using genome-wide significance, 37 CpGs and 47 regions were identified as differentially methylated (DM) in sarcoidosis compared to controls. Focusing on DE genes, we identified DM CpGs in 11 genes associated with sarcoidosis, 3 with SarcNP and 7 with SarcP. DIABLO first latent component distinguished cases and controls based on transcripts and CpGs associated with T cell signaling, T-cell differentiation, apoptosis, and epigenetic regulation. Among DE/DM transcripts identified by integrative omic analysis and validated by single cell RNA-seq is IL18 receptor accessory protein ( IL18RAP ). Conclusions: Integrative methylome–transcriptome profiling of lung CD4⁺ T cells identified coordinated immune and epigenetic alterations, including IL18RAP , as candidate biomarkers.
Funding Information
  • National Institutes of Health (R01ES023826)
  • National Institutes of Health (R01ES033678)
  • National Institutes of Health (R01ES034767)
  • National Institutes of Health (R01HL140357)
  • National Institutes of Health (R01HL153613)
  • National Institutes of Health (R01HL162955)
  • Anne Theodore Foundation (Breakthrough Sarcoidosis Initiative (ATF-BSI).)

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