As the first described miRNA,
lin-4 has been extensively studied as a member of the heterochronic gene pathway that regulates the timing of development in C. elegans. Overexpressing
lin-4 results in precocious phenotypes due to timing-related decisions of cell fate determination that are prematurely expedited. Contrarily,
lin-4 loss-of-function mutations, or gain-of-function mutations of the
lin-4-target,
lin-14, result in inappropriate reiterations of cellular division manifested by developmentally retarded phenotypes. In addition to functioning in the heterochronic gene pathway, our lab has recently shown that
lin-4 and
lin-14 play reciprocal post-developmental roles in regulating the lifespan of C. elegans. Despite all that is known about the function of
lin-4, little is known about the regulation of
lin-4 expression. Levels of
lin-4 miRNA are undetectable until the late L1 larval stage, indicating that
lin-4 is regulated temporally. Supporting this,
lin-4 expression appears to be down regulated over time in C. elegans adulthood. These patterns of
lin-4 expression are consistent with the reported functional roles of
lin-4 in development and aging. We are undertaking experiments designed to elucidate the mechanisms of
lin-4 regulation at the level of transcription. These experiments should: identify cis-regulatory elements important for temporal, and perhaps spatial, control over
lin-4 transcription; identify transcription factors that target the
lin-4 promoter; identify regulatory elements, cis or trans, that might differentiate between transcriptional regulation of
lin-4 in development and aging.