On-off switches: RNA interference and T1D

On-off switches: RNA interference and T1D

By: Shruthi Kandalai

Epigenetic changes or changes to DNA that do not affect the sequence itself, but can still impact gene activity, have been implicated in various diseases like T1D. Epigenetic changes may be a key to better understanding how T1D may be inherited in patients and could serve as future biomarkers for the condition. Among the types of epigenetic changes implicated in T1D are those related to RNA interference (RNAi), where RNA molecules interfere to neutralize mRNA and downregulate genes.

A study in C. elegans studied how epigenetic changes through RNAi could be inherited through populations.

  • Results found that epigenetic changes through RNAi specific to certain genes can be inherited and remain consistent through generations, though not all changes will be inherited.
  • Many of the RNA interference states were associated with heat shock factor 1 (HSF-1) activity, which has also been shown to be involved in transcription and regulation of transcriptome remodeling.

Specific microRNAs (miRNAs), a type of RNAi molecule, have also been implicated in T1D studies, as a research group showed by analyzing total RNA from the blood of newly diagnosed T1D patients.

  • Microanalysis found 91 miRNAs that were significantly deregulated in T1D patients compared to controls, with eight miRNAs having a fold change of more than 2 (one upregulated and seven downregulated).
  • A novel miRNA, miR-487a-3p, was found to be among the eight miRNAs with a larger fold change, with immune receptor CTLA4 and transcription factor FOXO3 being its targets.

A recent study aimed to profile RNA transcripts from human islet-derived vesicles in a model of T1D to understand how immune function may be impacted.

  • Results found that multiple classes of RNAi molecules were affected, including long noncoding RNAs (lncRNAs), microRNAs (miRNAs), piwi-interacting RNAs (piRNAs), transfer RNAs (tRNAs), and small nucleolar RNAs (snoRNAs), all of which may play a role in gene transcription.
    • Of these, lncRNAs and miRNAs were the most abundant.
  • While many different transcripts were implicated in the study, some of these RNA transcripts may play a role in disease progression and inheritance and could serve as future biomarkers of T1D.

The takeaway: Overall, these studies show that much about epigenetic inheritance and its role in T1D is still being understood and that epigenetic changes, including those focused on immune cells, have been implicated in T1D. Of the RNAi sequences found so far, some of these may be used as future biomarkers for the disease to detect T1D at earlier stages, though future research would be needed to support these efforts.

Sources:

  • Houri-Ze’Evi, L., Kohanim, Y. K., Antonova, O., & Rechavi, O. (2020). Three Rules Explain Transgenerational Small RNA Inheritance in C. elegans. Cell, 182(5), 1186-1197.
  • Zurawek, M., Dzikiewicz-Krawczyk, A., Izykowska, K., Ziolkowska-Suchanek, I., Skowronska, B., Czainska, M., . . . Nowak, J. (2018). MiR-487a-3p upregulated in type 1 diabetes targets CTLA4 and FOXO3. Diabetes Research and Clinical Practice, 142, 146-153.
  • Krishnan, P., Syed, F., Kang, N. J., Mirmira, R. G., & Evans-Molina, C. (2019). Profiling of RNAs from Human Islet-Derived Exosomes in a Model of Type 1 Diabetes. International Journal of Molecular Sciences, 20(23), 5903.

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