Cells have a number of different mechanisms, including RNAi, that can use the sequence information in small non-coding RNA molecules to direct an action or enzymatic process toward a specific DNA or mRNA sequence. These RNA-directed activities effectively regulate transcription, mRNA stability, mRNA translation, and defend cells against invading or foreign nucleic acids. Such mechanisms have profound influences on stem cell fate, development, chromosome functions, epigenetic programming, and genome integrity; not surprisingly, defects in the RNAi machinery are associated with developmental disorders and cancer. RNAi mechanisms are also responsive to environmental conditions and stress, although, how environmental conditions affect RNAi mechanisms is largely unknown.

Our research has led to the discovery that some ABC transporter proteins play a role in RNAi. ABC transporters are transmembrane proteins that pump small molecules across a membrane bilayer. Most organisms have many ABC transporter genes with diverse functions (humans have ~50 genes). Some allow for cellular detoxification; others function in multicellular organisms to facilitate the biosynthesis of essential compounds or maintain proper homeostasis of essential substances.

We are investigating precisely how trafficking by ABC transporters can influence RNAi mechanisms, how this might influence cell fate decisions in the germ line (the ultimate stem cell), and how transporter functions might relay environmental or dietary signals to changes in gene transcription via their effects on RNAi mechanisms. We also continue to develop RNAi techniques to enhance our ability to silence the expression of specific genes.

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