College of Arts and Sciences, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA.
Eye and Vision Science Laboratory, Department of Physiology, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
Mol Cell Biochem. 2021 Feb;476(2):663-673. doi: 10.1007/s11010-020-03934-0. Epub 2020 Oct 19.
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.
表观遗传记忆在基因调控中起着至关重要的作用。它不仅调节特定基因的表达，还对其他基因的转录和翻译产生连锁反应。通常，表达的改变要么通过甲基化或去甲基化发生，要么通过“一碳代谢”发生。在这种情况下，“一碳代谢”的失调就显得尤为重要，因为它会导致高同型半胱氨酸（Hcy，即高同型半胱氨酸血症，HHcy）的产生，而 Hcy 是蛋氨酸生物合成过程中“一碳代谢”的副产物，会对心血管、肾脏、脑血管系统以及许多其他疾病产生严重影响。目前，通过前体 mRNA 分子的非规范反向剪接事件产生的环状 RNA（circRNA）因其在疾病中的表观遗传表现而成为研究的中心。我们最近发现了一种环状 RNA 转录本（circGRM4），在胱硫醚β-合酶缺陷型小鼠的眼睛中显著上调。我们还发现这些小鼠眼睛中的 mGLUR4 受体同时过度表达。简而言之，circGRM4 是从其亲本 mGLUR4 受体基因（GRM4）中选择性转录的，作为 miRNA 的“分子海绵”，导致眼睛中 mGLUR4 受体的过度周转，以应对极高的循环谷氨酸浓度。我们认为，这种表观遗传表现可能使 HHcy 人群易患视网膜血管功能障碍。
