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

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 beta-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. [GRAPHICS] .

Automated summary

The article discusses the crucial roles of epigenetic memory in gene regulation, with a focus on the dysregulation of 1-carbon metabolism leading to hyperhomocysteinemia and various diseases. A circular RNA transcript, circGRM4, was found to be significantly upregulated in the eyes of cystathionine beta-synthase-deficient mice, potentially predisposing individuals with hyperhomocysteinemia to retinovascular malfunctioning.