MicroRNAs are an abundant class of small non-coding RNAs that regulate gene expression post-transcriptionally via anti-sense base pairing. Although microRNAs function in regulating a number of cellular events, very little is known about how the expression of microRNAs is regulated. We have conducted a yeast-one-hybrid screen to identify transcription factors that bind to the upstream region of the founding member of the microRNAs,
lin-4, and have identified a novel protein with a Zinc-finger FLYWCH DNA binding domain as an interactor of the DNA region upstream of
lin-4. RNAi-by-feeding of Y11D7A.12 results in the premature expression of
lin-4 during the embryonic stage as assessed by a
lin-4 transcriptional GFP reporter and Northern blot analysis. The simultaneous RNAi of both Y11D7A.12 and its C. elegans paralog, C26E6.2, enhances this precocious
lin-4 expression phenotype. A deletion mutant of Y11D7A.12 also results in the premature expression of
lin-4 as well as a low penetrance of morphological abnormal L1 larvae and early larval lethality. The double deletion mutant of Y11D7A.12 and C26E6.2 results in the complete penetrance of early larval lethality. This lethal phenotype is not suppressed by a
lin-4(lf) mutation, suggesting that Y11D7A.12 and C26E6.2 regulate the expression of other genes in addition to
lin-4. A more comprehensive yeast-one-hybrid screen using Y11D7A.12 and C26E6.2 suggest that these proteins also have roles in the regulation of additional microRNAs. GFP reporter transgenes and developmental Westerns indicate that Y11D7A1.2 and C26E6.2 are expressed primarily in embryos, suggesting that they function as negative temporal regulators of their target microRNAs early in development.