Maya Capelson, Ph.D.

Regulation of chromatin insulator proteins by ubiquitin and SUMO conjugation pathways. Chromatin insulators are a unique class of regulatory elements that are defined by their ability to block enhancers form acting on nearby promoters. They have been proposed to do so by scaffolding higher-order chromatin loops, but the precise mechanism of their action remains an enigma. My graduate work, carried out in the lab of Dr. Victor Corces, characterized two novel aspects of the activity of the Drosophila gypsy chromatin insulator. The first is a new protein component of the insulator complex, the E3 ubiquitin ligase dTopors, which was found to promote enhancer-blocking activity of gypsy insulators by regulating the physical clustering of insulator complexes in the nucleus (Capelson et al., Mol Cell 2005). The second is post-translational modification of gypsy insulator proteins by Small Ubiquitin-like Modifier (SUMO), which was found to antagonize insulator activity by interfering with self-interactions of insulator protein complexes (Capelson et al, EMBO J 2006). Together, this work provided further evidence to the model that chromatin insulators act by scaffolding higher-order organization of chromatin via nuclear clustering or self-interactions. The discovered involvement of post-translational modifications of insulator proteins introduced a novel mechanism by which organization of chromatin domains may be regulated during development or cellular responses.

• Capelson, M. and Corces, V.G. (2004) Boundary elements and nuclear organization.Biology of the Cell 96:617-629.
• Capelson, M. and Corces, V.G. (2005) The ubiquitin ligase dTopors directs the nuclear organization of a chromatin insulator.Molecular Cell 20:105-116.
• Capelson, M. and Corces, V.G. (2006) The SUMO conjugation pathway attenuates the activity of the gypsy chromatin insulator.EMBO Journal 25:1906-1914.

Genome-binding roles of nuclear pore proteins in regulation of transcription and chromatin. The Nuclear Pore Complex (NPC), which forms a channel through the nuclear envelope and consists of proteins termed Nucleoporins (Nups), has been extensively studied as the mediator of nucleo-cytoplasmic transport. In addition to their canonical transport roles, Nups have also been suggested to participate in transcriptional regulation, yet this function of the NPC had not been explored in animal cells at the time. My postdoctoral work in the lab of Dr. Martin Hetzer discovered the presence of NPC components at transcribing loci throughout the Drosophila genome and demonstrated a functional involvement of a subset of Nups in the transcriptional induction of their target genes during development (Capelson et al., Cell 2010). These findings have put forth an exciting possibility that metazoan NPC components play a crucial and hitherto unknown role in direct regulation of developmental transcription programs. In efforts to characterize this novel function of the NPC, my lab has recently identified an interaction between Nups and key epigenetic regulators, such as NSL and Trithorax complexes, which points to a likely mechanism by which Nups can influence gene expression (Pascual-Garcia et al., Cell Rep 2014). Furthermore, we uncovered an involvement of Nup98 in transcriptional regulation of developmentally critical Hox genes and are currently investigating how NPC-genome contacts contribute to tissue-specific gene expression patterns.

• Capelson, M. and Hetzer, M.W.  (2009) The Role of Nuclear Pores in Gene Regulation, Development and Disease.EMBO Reports 10:697-705.
• Capelson, M., Liang, Y., Schulte, R., Mair, W., Wagner, U. and Hetzer, M.W. (2010) Chromatin-bound nuclear pore components regulate gene expression in higher eukaryotes.Cell 140:372-382.
• Pascual-Garcia, P. and Capelson, M. (2014) Nuclear pores as versatile platforms for gene regulation.Curr Opin Genet Dev Apr; 25C:110-117.
• Pascual-Garcia, P., Jeong, J., Capelson, M. (2014) Nucleoporin Nup98 associates with Trx/MLL and NSL histone modifying complexes and regulates Hox gene expression.Cell Reports Oct 23; 9(2):433-42.