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 and how those changes impact phenotypic expression.
I have long been interested in the mechanisms of genome evolution, and especially in the functional impact of genome variation on gene regulation during development. 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) and TF networks 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 animal behaviors are species-unique, many behaviors, including many types of social response, are very deeply conserved in both expression and in the underlying mechanisms. In virtually all social species, exposure to social stimuli also elicits a learned response that shapes future behaviors. as members of a collaborative team of experimental and computational biologists in the UIUC institute for genomic biology (IGB), we have tested the hypothesis that learned social behaviors are regulated by common molecular molecular mechanisms in animals of diverse types. To test this notion, we have examined brain gene expression and chromatin accessibility after exposure to salient social interactions and compared active TFs and regulatory networks across behavioral model species.
Our work has confirmed that there are deep commonalities in mechanisms of social response across the animal kingdom - and revealed mechanisms including a conserved modulation of metabolic signaling and re-activation of regulatory programs most commonly associated with embryonic brain development. These studies have provided a first glimpse at conserved mechanisms underlying learned social response.
The Stubbs group is focused on validating and explicating these mechanisms using the mouse model system, which allows exploitation of rich genetics and genomics resources to further probe these ancient regulatory networks. We are exploring key TF nodes to discover their regulatory targets and to investigate how their genetic variation translates to differences in behavioral response. Since abnormal adaptation of social stimuli underlie many different types of neurological disorders, and since the mechanisms we are uncovering are so deeply conserved, these studies have significant potential to reveal the mechanisms of development and neural plasticity that are directly relevant to human health.
Mouse mutants that dissect the genome’s regulatory architecture
Vertebrate genomes are organized into "topologically associating domains", or TADs, that spatially group neighboring genes within the nucleus. Within these domains, regulatory elements may interact with local promoters, regardless of gene boundaries, and confer some level of co-regulation upon the neighboring genes. The classical tool for discovering these long-range regulatory effects and for linking distant regulatory elements with gene promoters has been genome rearrangements, such as translocations and deletions, which occur far from genes but yet disrupt their tissue-specific and/or temporal expression. These types of mutations are rare, but when they exist, provide valuable tools for dissecting the structure and function of extended and distant regulatory domains.
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, and showed that 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, was also operating in the germlines of the founder translocation mutant mice.
Our major interest is in the translocations mapping far from any gene sequence that disturb long-range regulatory architecture within TADs, and generate tissue-specific, "conditional" gene knockouts (KOs) of important developmental genes. We are investigating the effects of these mutations on neighboring clusters of co-expressed genes, and particularly those cases which closely model the effects of regulatory mutations associated with human neurological disorders. Most interestingly, these mutations have revealed novel functions for developmentally essential genes that are not recapitulated 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.
Weisner PA*, Chen C-Y*, Sun Y, Yoo J, Kao W-C, Zhang H, Baltz ET, Troy JM, and Stubbs LJ. A mouse mutation that dysregulates neighboring Galnt17 and Auts2 genes is associated with phenotypes related to the human AUTS2 syndrome. Genes, Genomes and Genetics, 2019, in press.
Negi S, Bolt CC, Zhang H, Stubbs L. An extended regulatory landscape drives Tbx18 activity in a variety of prostate-associated lineages. Dev Biol, 446:180-192, 2019.
*Saul MC, *Seward CH, Troy JM, Zhang H, Sloofman L, Lu H, Weisner PA, Caetano-Anolles D, Sun H, Zhao SD, Chandrasekaran S, Sinha S, Stubbs L. Transcriptional regulatory dynamics set the stage for a 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.