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Cannabidiol Regulates Gene Expression in Encephalitogenic T cells Using Histone Methylation and noncoding RNA during
Xiaoming Yang1, Marpe Bam1, Prakash S Nagarkatti1
1Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina Columbia, South Carolina, 29209, USA.
Abstract:
Cannabidiol (CBD) has been shown by our laboratory to attenuate experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In this study, we used microarray and next generation sequencing (NGS)-based approaches to determine whether CBD would alter genome-wide histone modification and gene expression in MOG sensitized lymphocytes. We compared H3K4me3 and H3K27me3 marks in CD4+ T cells from naïve, EAE and CBD treated EAE mice by ChIP-seq. Although the overall methylation level of these two histone marks did not change significantly, the signal intensity and coverage differed in individual genes, suggesting that CBD may modulate gene expression by altering histone methylation. Further analysis showed that these histone methylation signals were differentially enriched in the binding sites of certain transcription factors, such as ZNF143 and FoxA1, suggesting that these transcription factors may play important roles in CBD mediated immune modulation. Using microarray analysis, we found that the expression pattern of many EAE-induced genes was reversed by CBD treatment which was consistent with its effect on attenuating the clinical symptoms of EAE. A unique finding of this study was that the expression of many miRNAs and lncRNAs was dramatically affected by CBD. In summary, this study demonstrates that CBD suppresses inflammation through multiple mechanisms, from histone methylation to miRNA to lncRNA.
Insights
Cannabidiol (CBD) treatment suppresses inflammation in a multiple sclerosis (MS) model by altering gene expression and histone modifications in immune cells. This immune modulation involves changes in transcription factors, miRNAs, and lncRNAs.
Area of Science:
- Immunology
- Neuroscience
- Epigenetics
Background:
- Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system.
- Cannabidiol (CBD) has demonstrated potential in attenuating experimental autoimmune encephalomyelitis (EAE), an animal model for MS.
- The molecular mechanisms underlying CBD's therapeutic effects in EAE remain incompletely understood.
Purpose of the Study:
- To investigate the genome-wide effects of CBD on histone modifications and gene expression in lymphocytes from MOG-sensitized EAE mice.
- To identify specific epigenetic changes and gene expression patterns modulated by CBD treatment.
- To explore the role of transcription factors, miRNAs, and lncRNAs in CBD-mediated immune modulation.
Main Methods:
- ChIP-seq was employed to compare H3K4me3 and H3K27me3 histone marks in CD4+ T cells from naïve, EAE, and CBD-treated EAE mice.
- Microarray analysis was used to assess genome-wide gene expression profiles.
- Next-generation sequencing (NGS) was utilized to analyze miRNA and lncRNA expression.
Main Results:
- CBD treatment altered the signal intensity and coverage of H3K4me3 and H3K27me3 marks at specific genes, suggesting modulation of gene expression via histone modification.
- Histone methylation signals were differentially enriched at the binding sites of transcription factors like ZNF143 and FoxA1.
- CBD treatment reversed the expression patterns of many EAE-induced genes and significantly affected the expression of numerous miRNAs and lncRNAs.
Conclusions:
- CBD suppresses inflammation in the EAE model through multifaceted mechanisms involving epigenetic modifications and regulation of gene expression.
- CBD's action involves altering histone methylation patterns, influencing transcription factor binding, and modulating the expression of non-coding RNAs (miRNAs and lncRNAs).
- These findings provide novel insights into the molecular pathways targeted by CBD for immune modulation in the context of MS.
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