Regulation of the parental gene GRM4 by circGrm4 RNA transcript and glutamate-mediated neurovascular toxicity in eyes
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Regulation of the parental gene GRM4 by circGrm4 RNA transcript and glutamate‑mediated neurovascular toxicity in eyes Wintana Eyob1 · Akash K. George2 · Rubens P. Homme2 · Dragana Stanisic3 · Harpal Sandhu4 · Suresh C. Tyagi5 · Mahavir Singh2 Received: 8 May 2020 / Accepted: 7 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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 premRNA 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-synthasedeficient 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. Graphic abstract
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Vol.:(0123456789)
Molecular and Cellular Biochemistry
Keywords Circular RNA · Epigenetics · Gene regulation · Disease pathology · Visual system
Introduction The study on how various eye diseases induce blindness has been a low priority for many countries, especially in the developing part of the world [1]. Some examples of retinal diseases affecting vision are diabetic retinopathy (DR) and age-related macular degeneration, AMD [2]. Without a properly functioning retina, phototransduction cannot transpire within the eye. According to the World Health Organization (WHO), more cases of blindness are recognized in the underdeveloped countries. Thus, the examination of this issue in a variety of ways is critical to find solutions for the debilitating, blinding eyes disease such as AMD and DR to negate the increasing cases of blindness. The recent interest in the complexity of gene regulation via epigenetics through a wide range of specific circular RNA (circRNA) transcripts appears to be a missing piece in the link for retinal degradation and vision impairment including blindness. With the recent
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