Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing

Abstract

A hallmark of mammalian embryonic development is the widespread induction of microRNA (miRNA) expression. Surprisingly, the transcription of many of these small, noncoding RNAs is unchanged through development; rather, a post-transcriptional regulatory event prevents accumulation of the mature miRNA species. Here, we present a biochemical framework for the regulated production of the Let-7 family of miRNAs. Embryonic cells contain a Drosha Inhibitor that prevents processing of the Let-7 primary transcript. This inhibitor specifically binds to conserved nucleotides in the loop region of the Let-7 precursor, and competitor RNAs that mimic the binding site restore Let-7 processing. We have identified the Drosha Inhibitor as the embryonic stem cell specific protein Lin-28. Lin-28 has been previously implicated in developmental regulatory pathways in Caenorhabditis elegans, and it promotes reprogramming of human somatic cells into pluripotent stem cells. Our findings outline a microRNA post-transcriptional regulatory network and establish a novel role for the miRNA precursor loop in the regulated production of mature Let-7.

A genetic variant in the pre-miR-27a oncogene is associated with a reduced familial breast cancer risk

“…Consequently the cleavage by Drosha would be blocked, and the maturation process is thereby inhibited. Piskounova et al showed that some Drosha inhibitors such as Lin28, selectively bind to the terminal loop region of miRNA precursors and mediate the miRNA procession [53,54]. Thus, it is also possible that the [A]-[G] variant changes the binding affinity of some Drosha inhibitors and consequently affects the processing of miR-27a.…”

Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer

“…It has been shown to block the processing of let-7 microRNAs (Heo et al, 2008;Newman et al, 2008;Rybak et al, 2008;Viswanathan et al, 2008) as well as a handful of other microRNAs (Heo et al, 2009;Trabucchi et al, 2009). In addition, Lin28 has been reported by us and others to bind to a specific subset of mRNAs, including those for IGF-2, Oct4, and several cell cycle-related factors, thereby modulating their translation (Polesskaya et al, 2007;Qiu et al, 2009;.…”

Role of Ribosomal Protein RPS2 in Controlling let-7a Expression in Human Prostate Cancer

“…In attempts to understand how let-7 expression might be regulated, studies of embryonic stem cells and cancer cells have shown that LIN28 binds to the stem-loop region of let7a precursors and inhibits pre-let-7a-1 RNA processing (5,6). The implication is that specific proteins/factors might control miRNA expression to enable oncogene-dependent cell transformation.…”