Periodic Reporting for period 4 - cureCD (Function of long non-coding RNA in Crohn Disease Ulcer Pathogenesis)
Reporting period: 2022-11-01 to 2024-10-31
Crohn’s Disease (CD) is a chronic and relapsing condition that affects millions of people worldwide. The defining feature of CD is the presence of mucosal wounds (ulcers), which result from complex interactions among microbiota, immune cells, and gut epithelial cells. Achieving healing of these mucosal wounds is associated with better health outcomes, but this occurs in fewer than half of the cases. Therefore, it is crucial to identify tissue-specific targets that promote mucosal healing, enhance outcomes, and minimize adverse effects.
Long non-coding RNAs (lncRNAs) represent a large and diverse class of non-protein-coding genes that exhibit tissue-specific expression. They have been shown to play key regulatory roles in cellular functions, particularly in regulating immunity and inflammation. In our research, we identified several altered lncRNAs associated with CD in both epithelial and immune cells. To investigate their mechanisms of action, we developed novel model systems to explore their functions in relation to microbiota interactions. Our findings revealed that various lncRNAs regulate crucial epithelial functions vital for maintaining epithelial barrier integrity, which becomes altered during gut inflammation. For instance, HNF1A-AS1 is involved in regulating epithelial renewal, GATA6-AS1 affects metabolic and mitochondrial functions, and a reduction in LHFPL3-AS2 impacts epithelial polarity. We published these discoveries in several peer-reviewed scientific journals (https://www.habermanlab.sites.tau.ac.il/(opens in new window)). Because CD lncRNAs demonstrate high tissue specificity, they represent promising targets for potential future interventions with a lower risk of adverse effects.
Long non-coding RNAs (lncRNAs) represent a large and diverse class of non-protein-coding genes that exhibit tissue-specific expression. They have been shown to play key regulatory roles in cellular functions, particularly in regulating immunity and inflammation. In our research, we identified several altered lncRNAs associated with CD in both epithelial and immune cells. To investigate their mechanisms of action, we developed novel model systems to explore their functions in relation to microbiota interactions. Our findings revealed that various lncRNAs regulate crucial epithelial functions vital for maintaining epithelial barrier integrity, which becomes altered during gut inflammation. For instance, HNF1A-AS1 is involved in regulating epithelial renewal, GATA6-AS1 affects metabolic and mitochondrial functions, and a reduction in LHFPL3-AS2 impacts epithelial polarity. We published these discoveries in several peer-reviewed scientific journals (https://www.habermanlab.sites.tau.ac.il/(opens in new window)). Because CD lncRNAs demonstrate high tissue specificity, they represent promising targets for potential future interventions with a lower risk of adverse effects.
We identified altered expressions of long non-coding RNAs (lncRNAs) and protein-coding genes in Crohn’s Disease (CD) by analyzing human cohorts. We created a comprehensive atlas of dysregulated lncRNAs along the gastrointestinal (GI) tract (web interface: https://tzipi.shinyapps.io/lncRNA_gut(opens in new window)) and demonstrated cell-specific expression of prioritized lncRNAs in epithelial cells and granulocytes using available single-cell datasets.
Additionally, we prioritized potential regulatory epithelial lncRNAs based on omics analyses. We then explored their mechanisms in epithelial cells using specific knockdowns in various human-derived and murine models. Our findings indicate that multiple lncRNAs regulate diverse epithelial functions critical for maintaining barrier integrity, which are disrupted during gut inflammation. For example, HNF1A-AS1 regulates epithelial renewal (PMID: 37261910), GATA6-AS1 influences metabolic and mitochondrial functions (PMID: 36655602), and a reduction in LHFPL3-AS2 affects epithelial polarity (PMID: 37993670).
We conducted a meta-analysis to identify predominant shared microbial responses across various diseases, including a specific signal for inflammatory bowel disease. This analysis defined shared and CD-specific microbial alterations (PMID: 30741738). Such identification can be utilized to prioritize fecal samples that are more or less “healthy” based on the general microbial signal, while CD-specific taxa may have a more direct association with gut inflammation and disease pathogenesis. These findings can serve as biomarkers and potential targets for future interventions.
Additionally, we prioritized potential regulatory epithelial lncRNAs based on omics analyses. We then explored their mechanisms in epithelial cells using specific knockdowns in various human-derived and murine models. Our findings indicate that multiple lncRNAs regulate diverse epithelial functions critical for maintaining barrier integrity, which are disrupted during gut inflammation. For example, HNF1A-AS1 regulates epithelial renewal (PMID: 37261910), GATA6-AS1 influences metabolic and mitochondrial functions (PMID: 36655602), and a reduction in LHFPL3-AS2 affects epithelial polarity (PMID: 37993670).
We conducted a meta-analysis to identify predominant shared microbial responses across various diseases, including a specific signal for inflammatory bowel disease. This analysis defined shared and CD-specific microbial alterations (PMID: 30741738). Such identification can be utilized to prioritize fecal samples that are more or less “healthy” based on the general microbial signal, while CD-specific taxa may have a more direct association with gut inflammation and disease pathogenesis. These findings can serve as biomarkers and potential targets for future interventions.
Crohn’s Disease (CD) is a common chronic inflammatory condition that affects the gut mucosa. Current therapies primarily focus on immune suppression; however, only 30-50% of patients achieve clinical and mucosal remission with existing treatments. We have identified and prioritized specific new targets, including epithelial long non-coding RNAs and the microbiome, as potential interventions for CD. These strategies can be further explored in preclinical studies and combined with immune suppression to enhance outcomes for patients with CD.