R2402 Institute for Genomic Biology
Office: (217) 244-4000
Fax: (217) 244-1781
Mail to: Dept of Cell and Developmental Biology University of Illinois B107 601 S. Goodwin Avenue Urbana, IL 61801
Lisa J Stubbs
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. Working against a background of deep conservation, which can help define the fundamental mechanisms of development, the components that have undergone evolutionary change hold potential to explain biological differences between species, but also between different individuals in the same populations.
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 social responses, are very deeply conserved. In virtually all social species, exposure to social stimuli also elicits a learned response that shapes future interactions and future response. We are testing the hypothesis that fundamental aspects of social response, as well as learned social behaviors, are regulated by common molecular molecular mechanisms as part of large, collaborative team of experimental and computational biologists. Specifically, we are examining brain gene expression and chromatin accessibility after exposure to social interactions, with the goal of comparing regulatory networks across a very broad array of 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.
The KRAB zinc finger transcription factor family
While most vertebrate transcription factor (TF) genes are deeply conserved, one family of genes, encoding proteins with multiple zinc-fingers (ZNFs), stands our for its evolutionary diversity. ZNFs are the only class of TFs that varies extensively between different evolutionary lineages and also between individuals of the same population, making them excellent candidates for determining lineage-specific and individually-variant phenotypic traits.
We are developing methods to trace genes and biological pathways that are regulated by both the conserved and lineage-specific ZNF TFs, in order to understand their impact on species-specific and individual traits. We combine transgenic expression, siRNA knockdown, 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.
Mouse mutants as tools to dissect the genome’s regulatory architecture
Early in my career, I helped develop a unique collection of mouse mutants that carry reciprocal chromosome translocations. Over the years we have mapped and sequenced a number of 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.
Some of the translocations occur within genes, creating simple "knockout" (KO) mutations of those loci. However, several of the translocations map far from any gene sequence in large "gene desert" regions, and by disturbing the long-range regulatory architecture in this regions, generate tissue-specific, partial gene KOs of important developmental genes. These mutations provide clues to the locations of regulatory elements that are essential to developmental gene expression. But further, they provide "conditional" mutations that can reveal new functions for developmentally essential genes.
|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 "knockout" of Tbx18 by separating the gene from long-distance enhancers. 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 "knockout" of Tbx18 in somites and urogenital tissues (figure above). Our work has shown that 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).
Other mutants in our collection provide insight into regulation of genes linked to behavioral abnormalities including impaired sociability, seizure disorders, aggressive behavior, other neurodevelopmental phenotypes. These novel, conserved regulatory elements provide a new window to the genetic and epigenetic causes of related human disease. We are combining experimental methods such as chromatin immunoprecipitation (ChIP), together with mouse genetics, transgenic technologies, and bioinformatics approaches to locate and functionally characterize the long-distance elements to understand their functions and interactions with other chromatin elements throughout development.
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. Fields, C., Gernat, T., Caetano-Anolles, D., Kholina, N., and Stubbs, L. Gain, loss and divergence in primate zinc-finger genes: a rich resource for the evolution of regulatory differences between species. PLoS One 6:e21553, 2011.
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.
Huntley S., Baggott D.M., Hamilton A.T., Tran-Gyamfi M., Yang S., Kim J., Gordon L., Branscomb E., and Stubbs L. A comprehensive catalog of human KRAB-associated zinc finger genes: insights into the evolutionary history of a large family of transcriptional repressors. Genome Research 16:669-677, 2006.