Functional diversity of TNRC6A and TNRC6B in miRNA-mediated gene regulation

Abstract Trinucleotide repeat-containing 6A (TNRC6A) and TNRC6B—members of the GW182 protein family—are essential components of the microRNA (miRNA)-induced silencing complex that post-transcriptionally regulate gene expression. Although both proteins interact with argonaute proteins to mediate miRNA-directed gene silencing, their distinct subcellular localizations and tissue-specific expression patterns indicate functional divergence. We compared their expression profiles across 19,616 samples from 54 tissues and demonstrated that TNRC6A exhibited a 4.1-fold higher mean transcript expression level than that of TNRC6B, with a moderate correlation (r = 0.686). Additionally, TNRC6A was predominantly expressed in the brain, reproductive tissues, and endocrine organs, whereas TNRC6B is expressed uniformly across most tissues. Knockout (KO) and rescue analyses revealed distinct regulatory targets—412 and 309 genes were upregulated in TNRC6A- and TNRC6B-KO cells, respectively, and 164 and 136 genes were downregulated in cells overexpressing TNRC6A and TNRC6B, respectively. Pathway analysis revealed that TNRC6A predominantly regulates RNA processing and miRNA-mediated silencing, whereas TNRC6B modulates the mitogen-activated protein kinase and inflammatory responses. Shared targets were associated with apoptosis and proteostasis, indicating that TNRC6A and TNRC6B function cooperatively and distinctly in miRNA-mediated gene regulation.