Antagonistic role of hnRNP A1 and KSRP in the regulation of let-7a biogenesis.

Nature Structural & Molecular Biology
Gracjan Michlewski, Javier F Cáceres

Abstract

The pluripotency-promoting proteins Lin28a and Lin28b act as post-transcriptional repressors of let-7 miRNA biogenesis in undifferentiated embryonic stem cells. The levels of mature let-7a differ substantially in cells lacking Lin28 expression, indicating the existence of additional mechanism(s) of post-transcriptional regulation. Here, we present evidence supporting a role for heteronuclear ribonucleoprotein A1 (hnRNP A1) as a negative regulator of let-7a. HnRNP A1 binds the conserved terminal loop of pri-let-7a-1 and inhibits its processing by Drosha. Levels of mature let-7a negatively correlate with hnRNP A1 levels in somatic cell lines. Furthermore, hnRNP A1 depletion increased pri-let-7a-1 processing by cell extracts, whereas its ectopic expression decreased let-7a production in vivo. Finally, hnRNP A1 binding to let-7a interferes with the binding of KSRP, which is known to promote let-7a biogenesis. We propose that hnRNP A1 and KSRP have antagonistic roles in the post-transcriptional regulation of let-7a expression.

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Methods Mentioned

BETA
electrophoretic gel mobility shift
transfection
SELEX
in vitro transcription
PCR
electrophoresis

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