Context-specific regulation of cell survival by a miRNA-controlled BIM rheostat

Abstract

Knockout of the ubiquitously expressed miRNA-17∼92 cluster in mice produces a lethal developmental lung defect, skeletal abnormalities, and blocked B lymphopoiesis. A shared target of miR-17∼92 miRNAs is the pro-apoptotic protein BIM, central to life-death decisions in mammalian cells. To clarify the contribution of miR-17∼92:Bim interactions to the complex miR-17∼92 knockout phenotype, we used a system of conditional mutagenesis of the nine Bim 3 ′ UTR miR-17∼92 seed matches. Blocking miR-17∼92:Bim interactions early in development phenocopied the lethal lung phenotype of miR-17∼92 ablation and generated a skeletal kinky tail. In the hematopoietic system, instead of causing the predicted B cell developmental block, it produced a selective inability of B cells to resist cellular stress; and prevented B and T cell hyperplasia caused by Bim haploinsufficiency. Thus, the interaction of miR-17∼92 with a single target is essential for life, and BIM regulation by miRNAs serves as a rheostat controlling cell survival in specific physiological contexts.

MicroRNA‑25‑3p regulates human nucleus pulposus cell proliferation and apoptosis in intervertebral disc degeneration by targeting Bim

“…Bim is closely associated with the development and treatment of autoimmune diseases, degenerative diseases and tumors. Previous studies have demonstrated that Bim is a target gene for multiple mirnas (41,42). Previous studies have shown that Bim is a putative mir-24 target (43,44).…”

The Role of MicroRNAs in Development and Function of Regulatory T Cells – Lessons for a Better Understanding of MicroRNA Biology

“…In contrast, lung development was exclusively dependent on the miR-17∼92/Bim axis (58). These experiments highlight the likely sparseness of "master targets, " although their existence might be partially obscured by the time consuming and almost exceedingly vast experimental effort, given that each miRNA has hundreds of theoretically predicted targets.…”

“…Notably, neither heterozygous nor homozygous loss of Pten rescued the effects of miR-17∼92-deficiency in Treg cells (51). Furthermore, disruption of miR-17∼92 MREs in Bim had almost no effect on B-cell development, despite a prominent role of Bim in apoptosis of B-lineage cells (57)(58)(59).…”

“…Furthermore, disruption of miR-17∼92 MREs in Bim had almost no effect on B-cell development, despite a prominent role of Bim in apoptosis of B-lineage cells ( 57 – 59 ). In contrast, lung development was exclusively dependent on the miR-17∼92/Bim axis ( 58 ). These experiments highlight the likely sparseness of “master targets,” although their existence might be partially obscured by the time consuming and almost exceedingly vast experimental effort, given that each miRNA has hundreds of theoretically predicted targets.…”

Parallel genetics of regulatory sequencesin vivo

“…These use integration of reporters 13,14 or injection of RNA libraries 15,16 and therefore do not evaluate endogenous phenotypes, or are restricted to one stage of the animal life cycle. Classical genome editing by injection, now widely accessible due to CRISPR-Cas 17,18 , has enabled endogenous functional tests, but is still work-intensive and limited in scalability 19,20 .…”