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Our primary research interests are transcriptional and RNA regulatory mechanisms impacting mammalian fertility, neurological function, and cancer.

Homeobox gene circuits. The mouse Rhox gene cluster encodes homeobox transcription factors selectively expressed in embryonic stem (ES) cells, the developing embryo, and both germ cells and somatic cells in adult reproductive tissues. Using knockout, tissue-specific knockdown, and genome-wide ChIP approaches, we are elucidating the function and targets of Rhox genes. To determine their place in transcriptional networks, we are elucidating the factors and mechanisms controlling Rhox gene expression (e.g., androgen receptor, Ras signaling, H1 histones, DNA methylation, and transcriptional elongation). Epigenetic mechanisms are the focus of our ongoing studies. Our studies have the potential to lead to cures for infertility, novel contraceptive methods, and stem-cell therapeutic approaches.

RNA surveillance. The nonsense-mediated decay (NMD) pathway rapidly degrades aberrant mRNAs, thereby reducing the expression of the abnormal proteins with deleterious activities that would otherwise be produced. Such aberrant mRNAs are transcribed from mutant genes generated by random mutations and programmed gene rearrangements. Recently, it has become clear that NMD also regulates transcripts from many non-mutant genes. This suggests that NMD is an important regulator of normal gene expression during development and homeostasis, a hypothesis we are currently testing by employing knockout and knockdown approaches. Consistent with its important physiological role, we recently discovered that NMD is under tight regulatory control by microRNAs and components of the NMD pathway itself. Evidence suggests that disruption of these NMD regulatory circuits perturbs normal brain function.

Track(s):
MCB
Genetics