Information about the Stubbs Lab.


Stubbs LogoThe Stubbs Lab is interested in the mechanisms of gene regulation, especially long-range regulatory mechanisms, and on the phenotypic impact of variation in these mechanisms at the individual and species levels. We are particularly interested in the development and adult plasticity of tissues with the highest levels of intra- and interspecies diversity, especially the brain. To investigate the mechanisms underlying this diversity, we combine comparative genomics, mouse genetics, high-resolution imaging, chromatin-based methods, and bioinformatics analysis, with the goal of linking regulatory variation to specific morphological and behavioral traits.

Our current work is focused in two areas: 

  • Investigating the regulatory functions of transcription factor genes and networks associated with brain development and adult brain plasticity
  • Identifying conserved and species-variant components of the mammalian regulatory machinery, especially those components controlling brain development and adaptive brain plasticity in adults.  We are particularly interested in how variation in these genetic factors translates into behavioral differences.
  • Investigating the mechanisms through which disruption of conserved "gene neighborhoods," through genome rearrangements and other types of regulatory mutations, contributes to the complex genetics of brain development, behavior, and neurological disease.

Our Principal Investigator is Lisa J Stubbs.

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Research Interests
Molecular Roots of the Social Brain

This work has been conducted as a multi-disciplinary collaboration within the “Gene Networks in Neural & Developmental Plasticity” (GNDP) research theme at the Institute for Genomic Biology (IGB).  The Stubbs lab is working with other GNDP faculty to test the hypothesis that conserved genomic mechanisms underlie the brain response to salient social interactions across the animal kingdom.  To test this hypothesis, we have used a diverse range of established animal behavioral models –honey bees, stickleback fish, and mice – and the stringent filter of comparative genomics to uncover conserved neurogenomic signatures of adaptive social responses. Our core focus is on networks of transcription factors (TFs) and other chromatin interactors that may determine individual and interspecies variation in social behavior.

The goal of the GNDP theme’s efforts is to tie the evidence we extract from each species together into a fundamental model of social responsiveness, and to follow these leads to elaborate conserved neurogenomic mechanisms that are directly relevant to human disorders and disease.  Indeed, our studies so far have uncovered conserved genes, pathways, and TF networks that are activated by salient social stimuli in all three species, including many associated with human disease. 

Regulatory mutations associated with mouse phenotypes that model neurodevelopmental disorders

Many critical developmental regulators are involved in the differentiation of multipotent progenitor cell types and display especially dynamic expression patterns, as their differentiation roles are deployed across different spatial locations over developmental time.  In particular, many genes associated with neurodevelopmental disorders are involved in basic processes – the timely replication of neuron progenitor cells (NPC), their differentiation into neurons or glia, the outgrowth of neurites, or formation of synapses - events that occur at different times in each region of the developing brain.  The deployment of these factors at the right time and place requires the precise combinatorial action of enhancers, silencers, and other regulatory elements (REs) including some located significant genomic distances from the gene.  These REs interact with each other and target promoters through the formation of chromatin loops to specify the location, time, and circumstances of the genes’ expression.

The basic mechanisms of long-distance regulation are just now beginning to be revealed, and only a few distant enhancers have been described in detail so far.  However, genetic studies in humans and mice made it clear that distal REs play a much more prevalent role.

Classically, the relationship between essential genes and long-distance REs has been identified through mutations that either involve the REs themselves or that separate REs from their cognate promoters via genome rearrangements. Our own studies have leveraged a unique collection of mouse translocation mutants for this same purpose, focusing on mutations that occur far from genes, but give rise to dramatic developmental effects.  Most of the translocations we have identified are associated with neurological phenotypes, and closely model certain types of human neurodevelopmental disease.

A key example is the intense current focus of our group, a translocation called 16Gso that breaks between and dysregulates the neighboring Galnt17 and Auts2 genes. Mutations in this human region have been associated with intellectual disability (ID), autistic spectrum disorder (ASD), epilepsy, as well as depression, bipolar disorder and a wide range of neurological diseases, and the AUTS2 gene has been the major focus of attention. AUTS2 is a complex gene with isoforms that are involved in different aspects of basic neuron development. Like other essential developmental genes, AUTS2 is also expressed dynamically across the brain throughout development, reflecting the gene’s essential roles in neuron development. GALNT17 had not been characterized previously, but our data show that the gene is expressed very dynamically across the developing brain, and highly co-expressed with AUTS2. We hypothesize that the two genes operate within the same functional pathways and that their expression is coordinated by a shared system of REs spread across the genomic region. We are focused on determining the details of gene function in conditional-mutant mice and in cultured neurons, and also in the characterization of the regulatory domain that controls this “neighborhood” of co-expressed neurodevelopmental genes.

We are convinced that this research has broader implications, in that regulatory mutations within co-expressed gene “neighborhoods” (more formally called topologically associating domains, or TADs) could explain many aspects of phenotypic variation associated with human neurological disease.