ZBED6, a Novel Transcription Factor Derived from a Domesticated DNA Transposon Regulates IGF2 Expression and Muscle Growth

This study identifies a previously uncharacterized protein, encoded by a domesticated DNA transposon, called ZBED6 that regulates the expression of the insulin-like growth factor 2 (IGF2) gene, and possibly numerous others, in all placental mammals including human

Full-length myocilin (MYOC) protein is purified from mammalian cells as a dimer

Myocilin (MYOC) is the gene with mutations most commonly observed in glaucoma patients. MYOC protein collected from patients and analyzed under non-reducing conditions suggests that MYOC is not normally found in a monomeric form. MYOC was first reported almost 20 years ago; however, a technical challenge still faced by researchers is an inability to isolate full-length MYOC protein for experimental purposes. Herein we describe two methods by which to isolate sufficient quantities of full-length MYOC protein from mammalian cells. Analytical size exclusion chromatography of isolated full-length MYOC protein indicated that it is predominantly dimeric and we propose a structure for the MYOC dimer. By sharing methods to obtain full-length MYOC protein, we hope to provide researchers with a tool that has previously not been available. The ultimate goal of MYOC research is to understand this target so we can help the patient that carries a MYOC mutation retain vision and maintain quality of life

A functional screen of the epigenome identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers

Epigenetic dysregulation is an emerging hallmark of cancers, and the identification of recurrent somatic mutations in chromatin regulators implies a causal role for altered chromatin states in tumorigenesis. As the majority of epigenetic mutations are inactivating and thus do not present directly druggable targets, we reasoned that these mutations may alter the epigenomic state of cancer cells and thereby expose novel epigenetic vulnerabilities. To systematically search for epigenetic synthetic lethal interactions, we performed a deep coverage pooled shRNA screen across a large collection of cancer cell lines using a library targeting a diverse set of epigenetic regulators. Strikingly, this unbiased screen revealed that silencing of the SWI/SNF ATPase subunit BRM/SMARCA2, selectively inhibits the proliferation of BRG1-deficient cancer cells. The mammalian SWI/SNF complexes (mSWI/SNF) regulate chromatin structure through ATP-dependent nucleosome remodeling. Recent cancer genome studies have revealed a significant frequency of mutations in several components of the mSWI/SNF complexes including loss of the catalytic subunit BRG1 in non-small cell lung cancers. Our studies reveal that BRM knockdown selectively induced cell cycle arrest in BRG1-mutant cancer cells and significantly impaired the growth of BRG1-mutant lung tumor xenografts. BRM is the paralog of BRG1, suggesting a model in which mSWI/SNF mutations lead to a hypomorphic complex that promotes tumorigenesis but cannot tolerate complete inactivation. Therefore, our studies present BRM as an attractive therapeutic target in BRG1-mutant cancers