Wu Lab

Homolog pairing can influence gene expression through transvection, including the action of enhancers in trans. Using high-throughput FISH, we are conducting whole-genome screens for genes that control pairing. These studies have uncovered both pairing and anti-pairing activities, revealed a pairing-based signature that distinguishes the germ line from the soma early in embryogenesis, and brought us face-to-face with sister chromatid cohesion and the cell cycle. Most recently, we have begun applying Hi-C technologies to reveal the dynamic process of homolog pairing. (Joyce et al. 2012 Plos Genetics, Joyce et al. 2013 Plos Genetics, Senaratne et al. in preparation).

We develop technologies for visualizing chromosomes and revealing their organization within the nucleus. One such technology is Oligopaints, an oligo-based approach for FISH that can be used to image single copy regions as small as tens of kilobases and as large as tens of megabases. (Beliveau, Joyce et al. 2012 PNAS, Beliveau et al. 2014 Curr Protocols Mol Biol., Murgha et al. 2015 Biotechniques , Pinter et al. 2015 Genetics , Beliveau et al. 2015 Nat Comm.,)

HOPs, a strategy for distinguishing homologs: We have harnessed single nucleotide polymorphisms (SNPs) to enable a robust and reliable Oligopaint-based method for visually distinguishing the maternal and paternal homologous chromosomes in mammalian and insect systems. (Beliveau et al. 2015 Nat Comm).

OligoSTORM and OligoDNA-PAINT, two single-molecule super-resolution strategies for visulaizing the genome: We have melded Oligopaints with two single-molecule super-resolution strategies to enable the fine-scale in situ analysis of chromatin structure. Here, we have used Stochastic Optical Reconstruction Microscopy (STORM, in collaboration with the laboratory of Xiaowei Zhuang) and DNA-based Point Accumula-tion in Nanoscale Topography (DNA-PAINT, in collaboration with the laboratories of Peng Yin and Ralf Jungmann). (Beliveau et al. 2015 Nat Comm.)

The perfect conservation of UCEs between distantly related mammals has been a long-standing puzzle. Breaking from more popular models, we propose that UCEs maintain genome integrity via pairing and sequence comparison. We are testing this model using computational and wet bench strategies to reveal the relationship between UCEs and copy number variants (CNVs), selection pressure, and disease, such as cancer. (Derti et al. 2006 Nat Gen, Chiang et al. 2008 Genetics, McCole et al. 2014 Plos Genetics).

We have found that some genes of the PcG, which encode chromatin proteins, are important for pairing-associated phenotypes. Our work focusing on two such genes, Psc and Su(z)2, have identified several functional domains and provided evidence for intramolecular regulation. We are now exploring how Psc and Su(z)2 control gene expression both in vivo and in cell culture. (Emmons et al. 2009 Genetics, Nguyen et al. in preparation).

As part of the Consortium for Space Genetics (homepage), we are beginning to address issues of human health in space via two major lines of investigation. The first focuses on a strategy for combatting genome damage due to ionizing radiation. This effort stems from our study of UCEs (see above), which we predict hold a surprising potential to protect our genome from deleterious rearrangements. The second will explore the impact of extreme environments on chromatin structure. This effort will take advantage of our Oligopaint technologies, such as OligoSTORM and OligoDNA-PAINT, and examine the structure of the genome via in situ imaging of chromosomal DNA at ≤ 20 nm resolution (see above).

The laboratory is also interested in gene regulatory and chromosomal mechanisms that can cause a diploid cell to be functionally hemizygous at specific chromosomal loci or across an entire chromosome. These include mechanisms such as random mononallelism, parental imprinting, X-inactivation, and loss-of-heterozygosity through mitotic recombination. (Wu and Dunlap 2002 Adv. Gen., Wu and Williams 2004 Genetics, Savova et al. in preparation.)