Transcription of the C. elegans let-7 microRNA is temporally regulated by one of its targets, hbl-1

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
Developmental Biology (Impact Factor: 3.64). 08/2009; 334(2):523-34. DOI: 10.1016/j.ydbio.2009.07.012
Source: PubMed

ABSTRACT The let-7 family of microRNAs (miRNAs) are important regulators of developmental timing and cell differentiation and are often misexpressed in human cancer. In C. elegans, let-7 controls cell fate transitions from larval stage 4 (L4) to adulthood by post-transcriptionally down-regulating lineage-abnormal 41 (lin-41) and hunchback-like 1 (hbl-1). Primary let-7 (pri-let-7) transcripts are up-regulated in the L3, yet little is known about what controls this transcriptional up-regulation. We sought factors that either turn on let-7 transcription or keep it repressed until the correct time. Here we report that one of let-7's targets, the transcription factor Hunchback-like 1 (HBL-1), is responsible for inhibiting the transcription of let-7 in specific tissues until the L3. hbl-1 is a known developmental timing regulator and inhibits adult development in larval stages. Therefore, one important function of HBL-1 in maintaining larval stage fates is inhibition of let-7. Indeed, our results reveal let-7 as the first known target of the HBL-1 transcription factor in C. elegans and suggest a negative feedback loop mechanism for let-7 and HBL-1 regulation.

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Available from: Frank Slack, Jul 28, 2015
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    • "Student's t test) had completed this process (Fig. 4d–e and S4a). Similar delays were observed in strains containing two independent hbl-1 alleles (mg285 and ve18), both of which reduce but do not eliminate hbl-1 gene activity (Abrahante et al., 2003; Lin et al., 2003; Roush and Slack, 2009). The hbl-1 delayed remodeling defect was rescued by a transgene containing the F13D11 cosmid (which spans the hbl-1 gene; Fig. 4e). "
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    • "Another example of a shared target across species are Ras family proteins, which have essential roles in driving proliferation in early development (Koera et al., 1997), and which are targeted by let-7 from worms to humans (Johnson et al., 2005). These and other examples pinpoint let-7 as a key switch in shutting off the embryonic state (Roush and Slack, 2009). "
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    • "Later in larval development, members of the let-7 miRNA family control the L2-to-L3 and L4-to-adult transitions (Abbott et al., 2005; Esquela-Kerscher et al., 2005; Li et al., 2005; Reinhart et al., 2000) through the down-regulation of other heterochronic genes such as hbl-1 (Abrahante et al., 2003; Lin et al., 2003), lin-41 (Slack et al., 2000) and daf-12 (Grosshans et al., 2005). Recently, negative feedback networks between the let-7 family of miRNAs and their targets have been revealed, as daf-12 and hbl-1 regulate let-7 expression (Bethke et al., 2009; Hammell et al., 2009; Roush and Slack, 2009). The larva-to-adult (L/A) transition is controlled by the repression of hbl-1 and lin-41 through let-7, which in turn allows for the activation of lin-29. "
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