Single cell epigenomic profiling identifies a distinct classical monocyte subset driving inflammation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME) 4815

Abstract Description Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME) is a debilitating disease defined by overwhelming fatigue, cognitive dysfunction, flu-like symptoms, and post-exertional malaise (PEM), sharing many characteristics with infection associated chronic conditions (IACC) such as Long COVID. While its etiology remains unclear, we have previously implicated classical monocyte dysregulation, heightened inflammatory milieu, and transcriptional priming of T cells towards exhaustion in ME pathophysiology. Nonetheless, it remains unknown whether there are concordant changes between cell types for individual patients, and how the gene regulatory landscape is reshaped, especially during PEM. Thus, we generated single cell chromatin accessibility profiles of PBMCs at baseline and after PEM provocation by an exercise test. We identified a unique subpopulation of classical monocytes defined by lower CD14 accessibility and increased accessibility near genes associated with inflammation, and found that these genes are upregulated in ME patients. Moreover, we observed widespread reprogramming at transcription factor binding sites in monocytes and T cells, including upregulation of NF-kappa-B family TFs in monocytes. Funding Sources Supported by NIH U54NS105541; U54AI178855; Amar Foundation. Topic Categories Immune Mechanisms of Human Disease (HUM)