The Integrator complex regulates microRNA abundance through RISC loading

Abstract

MicroRNA (miRNA) homeostasis is crucial for the posttranscriptional regulation of their target genes during development and in disease states. miRNAs are derived from primary transcripts and are processed from a hairpin precursor intermediary to a mature 22-nucleotide duplex RNA. Loading of the duplex into the Argonaute (AGO) protein family is pivotal to miRNA abundance and its posttranscriptional function. The Integrator complex plays a key role in protein coding and noncoding RNA maturation, RNA polymerase II pause-release, and premature transcriptional termination. Here, we report that loss of Integrator results in global destabilization of mature miRNAs. Enhanced ultraviolet cross-linking and immunoprecipitation of Integrator uncovered an association with duplex miRNAs before their loading onto AGOs. Tracing miRNA fate from biogenesis to stabilization by incorporating 4-thiouridine in nascent transcripts pinpointed a critical role for Integrator in miRNA assembly into AGOs.

Differential regulation of miRNAs involved in the susceptible and resistance responses of wheat cultivars to wheat streak mosaic virus and Triticum mosaic virus

“…For miRNA 397, we were unable to characterize its potential targets; however from the literature we know it is involved in lignin biosynthesis, overexpression of it reduced the lignin deposition and increased susceptibility to fungal pathogens [ 23 ]. miRNA 398 targets integrator complex which has been found to regulate miRNA abundance [ 37 ], as well as superoxide dismutase which has been previously linked to several infections as both negative and positive regulator of the infection [ 38 , 39 ]. miRNA 5384-3p has the most targets of all miRNAs studied in this analysis, including transcription factors, autophagy related proteins, plant hormone transduction and several catalytic enzymes.…”

Rapid adaptation of cellular metabolic rate to the MicroRNA complements of mammals and its relevance to the evolution of endothermy

“… 169 Given the potential for microRNA regulation to increase the heritability of adaptive traits, 170 the enlargement of microRNA and target repertoires has been proposed as a key mechanism in the diversification of animal cell types and morphologies. 80 , 101 , 102 , 114 , 171 , 172 , 173 However, relatively little attention has been paid to the nature of global microRNA activity 55 , 56 , 174 , 175 , 176 or its relationship to cMR . 145 Our model predicts that compensatory noise suppression by microRNAs should be proportional to body temperature, since temperature is the primary determinant of the rate of protein synthesis, and therefore of intrinsic stochastic translation noise.…”

Rapid Adaptation of Cellular Metabolic Rate to the MicroRNA Complements of Mammals and its Relevance to the Evolution of Endothermy

“…Given the potential for microRNA regulation to increase the heritability of adaptive traits 171 , the enlargement of microRNA and target repertoires has been proposed as a key mechanism in the diversification of animal cell types and morphologies 81, 102, 103, 115, 172, 173, 174 . However, relatively little attention has been paid to the nature of global microRNA activity 55, 56, 175, 176, 177 or its relationship to cellular metabolic rate 146 . Our model predicts that compensatory noise suppression by microRNAs should be proportional to body temperature, since temperature is the primary determinant of the rate of protein synthesis, and therefore of intrinsic stochastic translation noise 46, 178 .…”

“…However, relatively little attention has been paid to the nature of global microRNA activity 55,56,175,176,177 or its relationship to cellular metabolic rate 146 . Our model predicts that compensatory noise suppression by microRNAs should be proportional to body temperature, since temperature is the primary determinant of the rate of protein synthesis, and therefore of intrinsic stochastic translation noise 46,178 .…”