Reciprocal regulation of miRNAs and piRNAs in embryonic development

Abstract

MicroRNAs (miRNAs) and piwi-interacting RNAs (piRNAs) are two classes of small noncoding RNAs, both of which play roles in regulating tissue development. It is unknown whether these distinct classes of noncoding RNAs can regulate one another. Here we show that ectopic expression of miR-17 inhibited mouse fertility and early embryonic development. Specifically, we found that the piRNA amplification loop was repressed by miR-17-5p, leading to increased levels of transposition mutagenesis. This occurred by suppressing the amplification loop of piRNAs with an identical 5′ sequence and by targeting Mili/Miwi2, an essential component of the piRNA amplification loop, and the DNA methyltransferase, Dnmt3a. We also found that increased levels of piRNAs could compete with miRNAs for target binding, resulting in increased expression of Dnmt3a and Mili. Increased Dnmt3a levels could in turn block miR-17-5p expression, while increased Mili expression could accelerate piRNA amplification and inhibit transposon generation, favoring embryonic development. We report for the first time the reciprocal regulation between miRNAs and piRNAs in mouse embryonic development. Cell Death and Differentiation (2016) 23, 1458-1470 doi:10.1038/cdd.2016; published online 18 March 2016A microRNA (miRNA) is a small non-coding RNA molecule of 18-24 nucleotides in length that are post-transcriptional regulators of gene expression. A miRNA has the capacity to affect the stability of hundreds of unique mRNAs 1 and may repress synthesis of hundreds of proteins by base-pairing with the targeting mRNAs. 2 The discovery of miRNAs in gene regulation has improved our understanding of posttranscriptional control of tissue development and aging. 3-5 A polycistronic miRNA cluster, miR-17~92, consisting of six mature miRNAs , and miR-92a-1), has been reported to play a fundamental role in development and remodeling. [6][7][8][9] Furthermore, members of miR-17-92 cluster are found to be commonly down-regulated in aging human cells. 10 We have found that ectopic expression of miR-17 retards tissue growth 11 and inhibits cell senescence. 12 Piwi-interacting RNA (piRNA) is the largest class of small non-coding RNAs expressed by animal cells. 13 piRNAs form complexes with piwi proteins, which function posttranscriptionally in silencing retrotransposons and other genetic elements in germ-line cells. 14 piRNA activity in gene regulation may lead to silencing of transposon expression, 15 as most piRNA sequences are antisense to transposon sequences. 16 The activity of piRNAs in transposon silencing appears to be the most important event during embryonic development. 17 To facilitate silencing transposons in the testes of mammals or in the germ cells of invertebrates, the piwi proteins play essential roles in interacting with piRNAs.These piwi proteins are members of Argonautes, proteins that are needed for gene silencing in miRNA action, including MIWI, MIWI2 and MILI. The sequences of piRNAs guide the piwi proteins to their transposon targets. 17 Decreased expressio...

The interaction of circRNAs and RNA binding proteins: An important part of circRNA maintenance and function

“…With the assistance of RBPs, an interesting example of this capacity is circ‐Amotl1, which can enhance wound repair by promoting cell proliferation, survival, adhesion, and migration (Yang, Awan et al, ). According to the prediction of a computational algorithm in a previous study, miR‐17‐5p is an excellent candidate for regulating RBP Stat3 expression and may also target the Dnmt3a gene to inhibit its expression (Du, Yang, Xuan et al, ). However, the increased cell activities occurred through Stat3 binding circ‐Amotl1 and enhancing nuclear translocation of Stat3.…”

In silicoanalysis of piRNAs in retina reveals potential targets in intracellular transport and retinal degeneration

“…It was surprising to find that piR-62011, an abundant piRNA in retina displayed seed sequence match and aligned completely with miR-182. Notably, seed sequence similarity between miR-17-5p and piRNAs has been shown to reciprocally regulate each other during mouse embryonic development 41 . However, the expression of miR-182 positively correlated with piR-62011.…”

“…Interestingly, seed sequence similarity between miR-17-5p and piRNAs has been shown to reciprocally regulate each other during mouse embryonic development 41 . It was surprising to find that piR-62011, an abundant piRNA in retina displayed seed sequence match and aligned completely with miR-182.…”

piRNAs Regulated by Mitochondria Variation Linked With Reproduction and Aging in Caenorhabditis elegans

“…Piwi protein has been found to bind specifically to a recently discovered type of non-coding RNA, named piRNA. This interaction has been found to play an important role in germline DNA integrity (Klattenhoff and Theurkauf, 2008), embryonic development (Du et al, 2016), immune defense [2] and cancer prediction (Zhang et al, 2016), etc. Moreover, piRNA also plays an important, albeit unknown, role in evolution (Parhad and Theurkauf, 2019).…”