Martin J Walsh, PhD

Perpetuation of cellular self -renewal by the ZNF217 oncogene-
ZNF21/zfp217 is an important oncogene in many cancer types. It impacts cell physiology markedly by shifting the apoptotic threshold of cancer cells causing resistance to the chemotherapeutical agent doxorubicin and contributing to telomere stability and immortalization under certain experimental conditions. While recent observations are clearly relevant to the understanding of ZNF217's role(s) in cancer, they represent an indirect effect through ZNF217's aggregate activity on the large number of genes that it targets. Little is known about how ZNF217 operates at the level of individual genes, i.e., about its principal mode(s) of molecular action as transcription factor. We have now demonstrated that ZNF217 forms a nuclear complex that can modify histones. Specifically, we documented H3K4me3 demethylation; H3K9 methylation; and H3K27 methylation. We identified five nuclear proteins contained in the ZNF217 complex, namely Jarid1b/Plu-1, a histone H3 lysine 4 (H3K4) tri-methyl demethylase; G9a, a principal euchromatic H3K9 methylase EZH2, a H3K27 methylase associated with the Polycomb Repressive Complex 2 (PRC2); LSD1, a H3K4 demethylase; CtBP1 and CoREST, which are both transcriptional co-repressors. Our studies illuminate the view that ZNF217 adopts a dynamic configuration of chromatin modifying enzymes to adapt to the localized chromatin environment. In collaboration with Dr. Gail Mandel's laboratory (Vollum Institute), we have now directed the ablation of the ZNF217 orthologue zfp217 in mouse embryonic stem cells

Epigenetic programming of Polycomb through long non -coding RNAs-
More recent studies investigate the regulation of the Polycomb group (PcG) and Trithorax (Trx) proteins in exerting gene control through the coordination of binding between long non-coding RNAs, histone lysine methylation and ubiquitination during early embryonic development and during oncogenesis. We have recently directed our effort to understand the role of long non-coding RNAs (ncRNAs) to mediate the function of Polycomb Repressive Complexes  (PRCs) 1 and 2. Transcription is pervasive through out the mammalian genome, however, most transcripts are non-coding in the genome but have been thought to impose an architectural function in chromatin Our recent studies have shown that ncRNAs are an instructional component of chromatin that mediates the function of PRC1 and PRC2 to further impose histone modifications for epigenetic gene silencing. Current studies by RNA ChIP-Seq are evaluating the role of ncRNAs that mask the human genome to coordinate PRC function during development and in human disease.