Description

Join us as Dr. Miranda Marvel, a post doctoral researcher from the NIH,  presents "A novel epigenetic regulator of arterial specification and development in zebrafish." This lecture was featured at the 22nd International Vascular Biology Meeting.  Abstract: Epigenetic mechanisms such as DNA and histone methylation play crucial roles in gene regulation and cell differentiation during development, but most vertebrate tissue-specific epigenetic regulators are still unknown. Our lab recently developed a novel “EpiTag” transgenic epigenetic reporter zebrafish line that reliably reports tissue-specific epigenetic silencing and activation via the expression of a destabilized green fluorescent protein (GFPd2). Using this line, we performed the first ever large-scale vertebrate forward genetic screen for epigenetic-related mutants and identified a mutant in an uncharacterized histone demethylase, Kdm4ab, with defects in vascular sprouting and arterial vessel development. Transcriptomic analysis of mutants identified many dysregulated angiogenic and arterial-specific genes, with many arterial-related genes exhibiting downregulation and venous-related genes showing an unexpected upregulation in mutant tissues. Further in situ experiments revealed the upregulated venous genes are ectopically expressed in arterial vessels in kdm4ab mutants. Analysis of histone methylation in kdm4ab mutants via CUT&RUN revealed that many vascular-related genes also have aberrantly increased H3K9me3 marks, suggesting they may be targets of Kdm4ab demethylase activity during development. Our ongoing experiments are currently elucidating the endothelial cell-autonomous roles of Kdm4ab in regulating arterial differentiation and development. Our preliminary findings suggest that Kdm4ab is a novel critical epigenetic regulator of arterial specification and development, and we are further characterizing the mechanisms of action of this histone demethylase.