Epigenetic mechanisms hold the key to developing novel therapeutic treatments for Ulcerative colitis

Background: Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC) and is associated with symptoms like abdominal pain, diarrhea, fatigue, reduced appetite, and weight loss. According to CDC, approx. 3 million Americans are reportedly diagnosed with IBD. Compared to normal individuals, IBD patients are more prone to colorectal cancer and arthritis. The causes of IBD are unknown; however, environmental, nutritional, microbiological, and genetic factors have been suggested to play a role in disease development. Nerve Growth Factor (NGF), a neurotrophic factor, is significantly elevated during several inflammatory and autoimmune diseases, including IBD and is essential for a robust inflammatory response. Studies suggest the importance of epigenetic mechanisms in chronic gastrointestinal inflammation and colorectal cancer, offering important insights into IBD's molecular basis. Although epigenetic regulators are well-explored in IBD, the regulations controlling NGF gene expression are unknown. Epigenetic modifications, including DNA methylation and covalent histone modifications, influence gene expression at the transcription level without altering the DNA sequence. We found that colon inflammation causes hypermethylation of the NGF promoter, resulting in its activation. Hypermethylation recruits proteins containing methylated DNA binding domains (MBDs), such as MeCP2. The evidence suggests that MeCP2 links DNA methylation and histone modifications to control gene expression.

Aim: To understand the involvement of MeCP2 and identify novel histone modifications associated with NGF transcription.

Method: TNBS-induced colitis animal model was used for this study. After inflammation, colon tissue was collected to study the DNA-protein and protein-protein interactions by Chromatin-immunoprecipitation-assay and Immunoprecipitation-assay, respectively.

Results and Conclusion: Our findings show that MeCP2 and tri-methylation of histone 3 lysine 4 (H3K4me3) are elevated during the TNBS-induced inflammation compared to control animals. ChIP and pull-down assays prove that MeCP2 interacts with H3K4me3, and both are associated with the hypermethylated NGF gene promoter for the active transcription during colon inflammation.