Epigenomic control of the molecular program underlying cardiac development

Multiple nups change in expression during differentiation, and one of the goals in the Faustino lab is to examine relationships, if any, between nup expression changes and putative roles in cardiac development. As some nups have emerged as epigenomic chromatin binding regulators, such interactions with pluripotent chromatin and/or dynamic remodeling of the transcriptome are two potential mechanisms by which nups may exert cardiogenic control. We use a platform of stem cell-derived cardiogenesis to survey RNA expression profiles (aka the transcriptome) of pluripotent embryonic stem cells (ESCs) as they differentiate into cardiomyocytes, and employ a combination of genome editing, network biology, cell biology and biochemical techniques to study this model of nup-driven cardiac systems biology.

 

Regulatory mechanisms of three dimensional genome dynamics

Select nups exist as a mobile pool and demonstrate the capacity to form discrete nuclear bodies in certain cell types. Nucleoplasmic nup-derived focal aggregations suggests a potential for epigenomic control of chromatin dynamics associated with these sub-nuclear nup-rich regions. As stem cell nuclei house a highly plastic genome, identification and investigation of potential mechanisms that regulate chromatin access will have implications for downstream molecular programming. We want to examine functions of nups as nucleoplasmic, membraneless organelles in a pluripotent niche using super-resolution microscopy, next generation sequencing, and molecular biology.

 

Nuclear mobility and its role in development

On the cytoplasmic side of the nuclear envelope, nups interact with the cytoskeleton to regulate nuclear positioning as stem cells differentiate. Nuclear locomotion can exert dramatic effects on cell fate acquisition, and in some cases are absolute requirements for terminal maturation. Genomic, transcriptomic, and proteomic elements involved in nuclear mobility have been identified and a role for nups is anticipated, but unexplored. To address this, stem cell culture and differentiation techniques, live cell confocal imaging, and targeted proteomics will be used as main experimental approaches to elucidate nup contribution(s) to nuclear movement.