Lisa J Stubbs
R2402 Institute for Genomic Biology
Office: (217) 244-4000
Fax: (217) 244-1781
Mail to: Dept of Cell and Developmental Biology University of Illinois
1206W. Gregory Dr. IGB2402, MC-195 Urbana, IL 61801
Professor of Cell and Developmental Biology
Chromatin Structure, Development, Genetics, Genomics, Molecular Evolution, Regulation of Gene Expression
B.S. University of Puget Sound (Biology)
Ph.D. University of California, San Diego (Biology)
Postdoc. California Institute of Technology, Pasadena CA; European Molecular Biology Laboratory, Heidelberg, Germany
Evolution of gene regulatory networks; Long-range regulatory mechanisms; Mouse models of human developmental disorders
Summary of Research Interests
Our research combines mouse genetics, bioinformatics and genomic methods to explore cis- and trans-acting components of mammalian gene regulatory machinery. We are particularly interested in how components of the regulatory machinery have been conserved, or have changed in specific lineages, over evolutionary time.
I have long been interested in the mechanisms of genome evolution, and especially in the functional impact of genome rearrangements, gene duplication and gene loss on species-specific aspects of gene regulation during development and differentiation. My group’s current work is focused on: (1) Examining regulatory mechanisms that control fundamental, conserved processes of development and postnatal phenotypic plasticity; (2) Investigating the interplay of conserved and species-variant transcription factors (TFs) in shaping this plasticity; and (3) Probing long-range gene regulatory mechanisms in mammals, using mouse mutants and genomic approaches to understand how these mechanisms contribute to plasticity and disease.
Ancient regulatory mechanisms control behavioral plasticity in diverse animal species
Although many types of animals behaviors are species-unique, certain types of behaviors, including many types of social response, are very deeply conserved. In virtually all social species, exposure to social stimuli also elicits a learned response that shapes future behaviors. We are testing the hypothesis that learned social behaviors are regulated by common molecular molecular mechanisms, as members of a collaborative team of experimental and computational biologists. Specifically, we are examining brain gene expression and chromatin accessibility after exposure to salient social interactions, with the goal of comparing regulatory networks across behavioral model species. Our work has revealed deep commonalities between species - including a conserved modulation of metabolic signaling and re-activation of mechanisms most commonly associated with embryonic brain development - that provide a first glimpse at conserved mechanisms underlying learned social response. The Stubbs group is focused on analysis of the mouse model system, including exploitation of the rich mouse genetics and genomics resources to further probe these ancient regulatory networks that underlie social response and behavioral plasticity.
Mouse mutants that dissect the genome’s regulatory architecture
Early in my career, I helped develop a unique collection of mouse mutants, each carrying distinct reciprocal chromosome translocations. We have mapped and sequenced the translocation breakpoints, revealing simple DNA "breakage and reunion" events with molecular signatures of non-homologous end-joining, a repair mechanism also associated with translocations occurring in somatic tissues.
A few of the translocations occur within genes, creating simple "knockout" (KO) mutations of those loci. However, our major interest is in the translocations mapping far from any gene sequence that, by disturbing the long-range regulatory architecture in these regions, generate tissue-specific, "conditional" gene knockouts (KOs) of important developmental genes. These mutations provide clues to the three-dimensional regulatory structures that are essential to coordinating developmental gene expression across the genome. And most interestingly, these mutations can reveal new functions for developmentally essential genes that are not revealed by simple KO mutations.
|12Gso, a reciprocal translocation involving chromosomes 4 and 9, is associated with recessive skeletal development, kidney, and reproductive defects (left). The mutation produces a tissue-specific KO of Tbx18 by separating the gene from long-distance enhancers, including a urogenital enhancer that our group has recently characterized. Because translocations involve obvious changes in chromosome structure, they can be visualized and mapped with fluorescent in situ hybridization, or FISH (right).|
An example is the 12Gso mutation, which is located more than 80 kb downstream of the Tbx18 transcription factor gene; mice inheriting this mutation display a tissue-specific KO of Tbx18 in somites and urogenital tissues (figure above). 12Gso acts by separating Tbx18 from an essential enhancer, called ECR1, that is required to drive gene expression in urogenital tissues. Other enhancers required for somite development are likely to be located further downstream (Bolt et al., 2014). These novel, conserved regulatory elements provide a new window to the genetic and epigenetic causes of related human disease.
Other mutants in our collection provide insight into the regulation of genes linked to behavioral abnormalities including impaired sociability, seizure disorders, aggressive behavior, other neurodevelopmental phenotypes. We are combining experimental methods such as chromatin immunoprecipitation (ChIP) and chromatin conformation capture (4C), together with mouse genetics and bioinformatics approaches to understand regulatory architectures that control the complex expression patterns and functions of these essential neurodevelopmental genes.
Rapidly evolving transcription factor genes
A long-standing interest of our group is the evolution of transcription factor (TF) genes and the role of TF diversity in species and individual differences. While most vertebrate TFs are deeply conserved, the large family of zinc-finger TFs (ZNFs) stand out for its evolutionary diversity. Because of this diversity, ZNF TFs are excellent candidates as factors determining lineage-specific and individually-variant phenotypic traits.
We combine mouse genetics, siRNA knockdown, CRISPR-based epitope tagging, chromatin immunoprecipation and bioinformatics to identify target genes, binding sites and the regulatory networks for these ZNF proteins. Our aim is to understand the impact of ZNF gene gain, loss and sequence divergence on vertebrate evolution, intraspecies variation, and human health.
*Saul MC, *Seward CH, Troy JM, Zhang H, Sloofman LG, Lu X, Weinser PA, Caetano-Anolles D, Sun H, Zhao SD, Chandrasekaran S, Sinha S, Stubbs L. Transcriptional regulatory dynamics drive coordinated metabolic and neural response to social challenge in mice. Genome Res, 27:959-972, 2017.
*Bolt CC, *Negi S, Guimarães-Camboa N, Zhang H, Troy JM, Lu X, Kispert A, Evans SM, Stubbs L. Tbx18 regulates the differentiation of periductal smooth muscle stroma and the maintenance of epithelial integrity in the prostate. PLoS One 11:e0154413, 2016.
Sun Y, Zhang H, Kazemian M, Troy JM, Seward C, Lu X, and Stubbs L. ZSCAN5B and primate-specific paralogs bind RNA polymerase III genes and extra-TFIIIC (ETC) sites to modulate mitotic progression. Oncotarget (Chromosome Section), 7(45): 72571-72592, 2016.
Rittschof, CC, Bukhari SA, Caetano-Anolles D, Cash-Ahmed A, Kent M, Lu X, Sanogo O, Sloofman L, Troy JM, Weinser PA, Zhang H, Bell AM, Sinha S, Robinson GE, Stubbs L. Neuromolecular responses to social challenge: common mechanisms across mouse, stickleback fish and honey bee. Proc Acad Sci USA 111:17929-17934, 2014.
Bolt CC, Elso CM, Lu X, Pan F, Kispert A, and Stubbs L. A distant downstream enhancers directs essential expression of Tbx18 in urogenital tissues. Devel Biol 392: 483-493, 2014.
Liu H, Chang L-H, Sun Y, Lu X and Stubbs, L. Deep vertebrate roots for mammalian zinc-finger transcription factor subfamilies. Genome Biol Evol 6:510-525, 2014.
Elso C, Lu X, Thompson HL, Weisner PA, Skinner A, Carver EA, and Stubbs L. A reciprocal translocation dissects functions of Pax6 alternative promoters and regulatory elements in development of pancreas, brain and eye. Genesis 51:630-646, 2013.
Nowick K, Hamilton AT, Zhang H, and Stubbs L. Rapid sequence and expression divergence suggests selection for novel function in primate-specific KRAB-ZNF genes. Mol Biol Evol 27:2606-2617, 2010.
Nowick, K. and Stubbs, L. Differences in human and chimpanzee gene expression patterns define an evolving network of transcription factors in brain. Proc Natl Acad Sci USA 106: 22358-22363, 2009.