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Regulation of the parental gene GRM4 by circGrm4 RNA transcript and glutamate-mediated neurovascular toxicity in eyes

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Abstract

Epigenetic memory plays crucial roles in gene regulation. It not only modulates the expression of specific genes but also has ripple effects on transcription as well as translation of other genes. Very often an alteration in expression occurs either via methylation or demethylation. In this context, “1-carbon metabolism” assumes a special significance since its dysregulation by higher levels of homocysteine; Hcy (known as hyperhomocysteinemia; HHcy), a byproduct of “1-Carbon Metabolism” during methionine biosynthesis leads to serious implications in cardiovascular, renal, cerebrovascular systems, and a host of other conditions. Currently, the circular RNAs (circRNAs) generated via non-canonical back-splicing events from the pre-mRNA molecules are at the center stage for their essential roles in diseases via their epigenetic manifestations. We recently identified a circular RNA transcript (circGRM4) that is significantly upregulated in the eye of cystathionine β-synthase-deficient mice. We also discovered a concurrent over-expression of the mGLUR4 receptor in the eyes of these mice. In brief, circGRM4 is selectively transcribed from its parental mGLUR4 receptor gene (GRM4) functions as a “molecular-sponge” for the miRNAs and results into excessive turnover of the mGLUR4 receptor in the eye in response to extremely high circulating glutamate concentration. We opine that this epigenetic manifestation potentially predisposes HHcy people to retinovascular malfunctioning.

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Acknowledgements

The authors would like to thank all members of the laboratory for their continuous help and excellent support. The part of this study was supported by NIH Grants, HL139047, AR-71789, and DK116591.

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Authors and Affiliations

  1. College of Arts and Sciences, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA

    Wintana Eyob

  2. Eye and Vision Science Laboratory, Department of Physiology, University of Louisville School of Medicine, Louisville, KY, 40202, USA

    Akash K. George, Rubens P. Homme & Mahavir Singh

  3. Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

    Dragana Stanisic

  4. Department of Ophthalmology and Visual Sciences and Kentucky Lions Eye Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA

    Harpal Sandhu

  5. Department of Physiology, University of Louisville School of Medicine, Louisville, KY, 40202, USA

    Suresh C. Tyagi

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MS conceived, edited, and finalized the manuscript while WE and AKG worked on the experiments and drafted the manuscript. The other co-authors helped in providing reagents and the feedback in moving the project forward. All authors approved the final version of the manuscript before its submission.

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Correspondence to Mahavir Singh.

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Eyob, W., George, A.K., Homme, R.P. et al. Regulation of the parental gene GRM4 by circGrm4 RNA transcript and glutamate-mediated neurovascular toxicity in eyes. Mol Cell Biochem 476, 663–673 (2021). https://doi.org/10.1007/s11010-020-03934-0

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