Redundant and incoherent regulations of multiple phenotypes suggest microRNAs’ role in stability control

Abstract

Each microRNA (miRNA) represses a web of target genes and, through them, controls multiple phenotypes. The difficulties inherent in such controls cast doubt on how effective miRNAs are in driving phenotypic changes. A "simple regulation" model posits "one target-one phenotype" control under which most targeting is nonfunctional. In an alternative "coordinate regulation" model, multiple targets are assumed to control the same phenotypes coherently, and most targeting is functional. Both models have some empirical support but pose different conceptual challenges. Here, we concurrently analyze multiple targets and phenotypes associated with the miRNA-310 family (miR310s) of Phenotypic rescue in the knockout background is achieved by promoter-directed RNA interference that restores wild-type expression. For one phenotype (eggshell morphology), we observed redundant regulation, hence rejecting "simple regulation" in favor of the "coordinate regulation" model. For other phenotypes (egg-hatching and male fertility), however, one gene shows full rescue, but three other rescues aggravate the phenotype. Overall, phenotypic controls by miR310s do not support either model. Like a thermostat that controls both heating and cooling elements to regulate temperature, redundancy and incoherence in regulation generally suggest some capacity in stability control. Our results therefore support the published view that miRNAs play a role in the canalization of transcriptome and, hence, phenotypes.

Run or die in the evolution of new microRNAs - Testing the Red Queen hypothesis on de novo new genes

“…Progeny count was taken after each of two consecutive rounds of mating (see Materials and Methods). As partial sperm depletion is more likely to happen in the second round, the latter measurement may be a more sensitive detector of male fertility differences (Liufu, et al 2017). To our surprise, the miR-983 KO males are more fertile than (or at least as fertile as) the control under several conditions ( Fig.…”

Impaired adult hippocampal neurogenesis in Alzheimer’s disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement

“…Differential gene expression analysis between miR-132-overexpressing and control cells within each cluster did not reveal any significantly deregulated transcripts after correction for multiple testing comparisons (Table S6), an observation that could be indicative of the frequently documented limited effect sizes of microRNA regulation (Moore et al, 2015). Since microRNAs may elicit changes on cellular dynamics via widespread, yet subtle effects on the transcriptome (Liufu et al, 2017), we next assessed the possible impact of miR-132 overexpression on molecular pathway regulation through gene set analysis. Gene ontology (GO) enrichment analysis using Ingenuity Pathway Analysis (IPA, Ingenuity Systems Inc., Redwood City, CA, USA) identified significantly enriched pathways upon miR-132 overexpression in each of the seven cell subpopulations (Figure S7D), suggesting that miR-132 regulation, although subtle at the single-gene level, may concomitantly impact diverse cellular processes.…”

“…Although these studies revealed trends for regulation of transcripts in several cell types, these changes did not reach statistical significance. The inherent challenges of characterizing direct microRNA targets is well acknowledged (Liufu et al, 2017) and likely reflect the subtle pleiotropic roles of miR-132 in the adult neurogenic niche. Given these limitations, we decided to validate possible regulatory interactions in human neural stem cells in vitro .…”

Transcriptional memory in skeletal muscle. Don't forget (to) exercise

“…In these fields, the reader is referred to excellent reviews published recently (Domanska‐Senderowska et al, 2019; Kirby, Chaillou, & McCarthy, 2015; Margolis & Rivas, 2018; Ultimo et al, 2018). At present, deciphering the true implications of miRNAs in skeletal muscle adaptation and memory modules is puzzling as each miRNA potentially targets a large number of genes, indicating substantial pleiotropic functional redundancy (Eichhorn et al, 2014; Liufu et al, 2017). Many miRNAs belong to multigene families, which are predicted to target the same (or overlapping) sets of genes, and multiple miRNAs may work as miRNA modules to synergistically regulate common target mRNAs (Ding, Li, & Hu, 2015).…”