Mechanisms of Lin28-Mediated miRNA and mRNA Regulation—A Structural and Functional Perspective

Abstract

Lin28 is an essential RNA-binding protein that is ubiquitously expressed in embryonic stem cells. Its physiological function has been linked to the regulation of differentiation, development, and oncogenesis as well as glucose metabolism. Lin28 mediates these pleiotropic functions by inhibiting let-7 miRNA biogenesis and by modulating the translation of target mRNAs. Both activities strongly depend on Lin28’s RNA-binding domains (RBDs), an N-terminal cold-shock domain (CSD) and a C-terminal Zn-knuckle domain (ZKD). Recent biochemical and structural studies revealed the mechanisms of how Lin28 controls let-7 biogenesis. Lin28 binds to the terminal loop of pri- and pre-let-7 miRNA and represses their processing by Drosha and Dicer. Several biochemical and structural studies showed that the specificity of this interaction is mainly mediated by the ZKD with a conserved GGAGA or GGAGA-like motif. Further RNA crosslinking and immunoprecipitation coupled to high-throughput sequencing (CLIP-seq) studies confirmed this binding motif and uncovered a large number of new mRNA binding sites. Here we review exciting recent progress in our understanding of how Lin28 binds structurally diverse RNAs and fulfills its pleiotropic functions.

LIN28: roles and regulation in development and beyond

“…Accordingly, a number of genetic pathways have been discovered in which LIN28 influences development via its regulation of let-7. The molecular aspects of the LIN28/let-7 axis have been studied in exquisite detail (Loughlin et al, 2012;Mayr and Heinemann, 2013;Nam et al, 2011). In brief, studies have shown that LIN28 can bind to both pri-and pre-let-7 in vivo and block their processing (Fig.…”

“…Once oligo-uridylated, pre-let-7 is more rapidly degraded than unmodified pre-let-7 (Heo et al, 2008), and it has been shown that, in mouse ESCs, the 3′-5′ exonuclease DIS3L12 catalyzes the decay of oligo-uridylated pre-let-7 . For a recent, in-depth review of LIN28-mediated control of let-7, the reader is referred to Mayr and Heinemann (2013).…”

IKBKE promotes glioblastoma progression by establishing the regulatory feedback loop of IKBKE/YAP1/miR-Let-7b/i

“…30,31 Recent studies simultaneously showed that miR-let-7 was mainly regulated by LIN28, an important RNA binding protein, targeting prelet-7 to block its maturity, thus facilitating carcinogenesis. [32][33][34] Meanwhile, Chaulk et al 35 recently showed that YAP1 successfully decreased mature let-7 expression by regulating the LIN28/Let-7 axis in breast cancer cell lines. Interestingly, YAP1 inhibition did not decrease mRNA expression of LIN28 but markedly decreased LIN28 protein expression, indicating that YAP1 may regulate LIN28 through post-transcriptional events, therefore, to reduce mature let-7 expression with no effect on pre-let-7.…”

Role of microRNAs in spermatogenesis

“…Интересно отметить, что удаление кластера генов микроРНК-17-92 приводит к увеличе-нию экспрессии другого кластера генов микро РНК-106b-25, также избирательно экспрессирующегося в не-дифференцированных спермато гониях, что, по всей видимости, указывает на их функциональное сотруд-ничество [68]. Показано, что при дифференцировке сперматогониев снижается регуляция семейством микроРНК let-7 таргетных целей мРНК Mycn, Ccnd1 и Colla2 [69][70][71][72][73][74][75].…”