A Mouse Mutation That Dysregulates Neighboring Galnt17 and Auts2 Genes Is Associated with Phenotypes Related to the Human AUTS2 Syndrome.

Weisner PA, Chen CY, Sun Y, Yoo J, Kao WC, Zhang H, Baltz ET, Troy JMStubbs L


AUTS2 was originally discovered as the gene disrupted by a translocation in human twins with Autism spectrum disorder, intellectual disability, and epilepsy. Since that initial finding, AUTS2-linked mutations and variants have been associated with a very broad array of neuropsychiatric disorders, suggesting that AUTS2 is required for fundamental steps of neurodevelopment. However, genotype-phenotype correlations in this region are complicated, because most mutations could also involve neighboring genes. Of particular interest is the nearest downstream neighbor of AUTS2,GALNT17, which encodes a brain-expressed N-acetylgalactosaminyltransferase of unknown brain function. Here we describe a mouse (Mus musculus) mutation, T(5G2;8A1)GSO (abbreviated 16Gso), a reciprocal translocation that breaks between Auts2 and Galnt17 and dysregulates both genes. Despite this complex regulatory effect, 16Gso homozygotes model certain human AUTS2-linked phenotypes very well. In addition to abnormalities in growth, craniofacial structure, learning and memory, and behavior, 16Gso homozygotes display distinct pathologies of the cerebellum and hippocampus that are similar to those associated with autism and other types of AUTS2-linked neurological disease. Analyzing mutant cerebellar and hippocampal transcriptomes to explain this pathology, we identified disturbances in pathways related to neuron and synapse maturation, neurotransmitter signaling, and cellular stress, suggesting possible cellular mechanisms. These pathways, coupled with the translocation’s selective effects on Auts2 isoforms and coordinated dysregulation of Galnt17, suggest novel hypotheses regarding the etiology of the human “AUTS2 syndrome” and the wide array of neurodevelopmental disorders linked to variance in this genomic region.

Read more at G3

An extended regulatory landscape drives Tbx18 activity in a variety of prostate-associated cell lineages.

Negi S, Bolt CC, Zhang HStubbs L


The evolutionarily conserved transcription factor, Tbx18, is expressed in a dynamic pattern throughout embryonic and early postnatal life and plays crucial roles in the development of multiple organ systems. Previous studies have indicated that this dynamic function is controlled by an expansive regulatory structure, extending far upstream and downstream of the gene. With the goal of identifying elements that interact with the Tbx18 promoter in developing prostate, we coupled chromatin conformation capture (4C) and ATAC-seq from embryonic day 18.5 (E18.5) mouse urogenital sinus (UGS), where Tbx18 is highly expressed. The data revealed dozens of active chromatin elements distributed throughout a 1.5 million base pair topologically associating domain (TAD). To identify cell types contributing to this chromatin signal, we used lineage tracing methods with a Tbx18 Cre “knock-in” allele; these data show clearly that Tbx18-expressing precursors differentiate into wide array of cell types in multiple tissue compartments, most of which have not been previously reported. We also used a 209 kb Cre-expressing Tbx18 transgene, to partition enhancers for specific precursor types into two rough spatial domains. Within this central 209 kb compartment, we identified ECR1, previously described to regulate Tbx18 expression in ureter, as an active regulator of UGS expression. Together these data define the diverse fates of Tbx18+ precursors in prostate-associated tissues for the first time, and identify a highly active TAD controlling the gene’s essential function in this tissue.

Read More at Developmental Biology

Honey bee neurogenomic responses to affiliative and agonistic social interactions

Hagai Y. Shpigler, Michael C. Saul, Emma E. Murdoch, Frida Corona, Amy C. Cash‐Ahmed, Christopher H. Seward, Sriram Chandrasekaran, Lisa J. Stubbs, Gene E. Robinson


Social interactions can be divided into two categories, affiliative and agonistic. How neurogenomic responses reflect these opposing valences is a central question in the biological embedding of experience. To address this question, we exposed honey bees to a queen larva, which evokes nursing, an affiliative alloparenting interaction, and measured the transcriptomic response of the mushroom body brain region at different times after exposure. Hundreds of genes were differentially expressed at distinct time points, revealing a dynamic temporal patterning of the response. Comparing these results to our previously published research on agonistic aggressive interactions, we found both shared and unique transcriptomic responses to each interaction. The commonly responding gene set was enriched for nuclear receptor signaling, the set specific to nursing was enriched for olfaction and neuron differentiation, and the set enriched for aggression was enriched for cytoskeleton, metabolism, and chromosome organization. Whole brain histone profiling after the affiliative interaction revealed few changes in chromatin accessibility, suggesting that the transcriptomic changes derive from already accessible areas of the genome. Although only one stimulus of each type was studied, we suggest that elements of the observed transcriptomic responses reflect molecular encoding of stimulus valence, thus priming individuals for future encounters. This hypothesis is supported by behavioral analyses showing that bees responding to either the affiliative or agonistic stimulus exhibited a higher probability of repeating the same behavior but a lower probability of performing the opposite behavior. These findings add to our understanding of the biological embedding at the molecular level.

Read More at G2B

Cross‐species systems analysis of evolutionary toolkits of neurogenomic response to social challenge

Michael C. SaulCharles BlattiWei YangSyed Abbas BukhariHagai Y. ShpiglerJoseph M. TroyChristopher H. SewardLaura G. SloofmanSriram ChandrasekaranAlison M. BellLisa J. StubbsGene E. RobinsonSihai Dave ZhaoSaurabh Sinha


Social challenges like territorial intrusions evoke behavioral responses in widely diverging species. Recent work has showed that evolutionary “toolkits”-genes and modules with lineage-specific variations but deep conservation of function-participate in the behavioral response to social challenge. Here, we develop a multispecies computational-experimental approach to characterize such a toolkit at a systems level. Brain transcriptomic responses to social challenge was probed via RNA-seq profiling in three diverged species-honey bees, mice and three-spined stickleback fish-following a common methodology, allowing fair comparisons across species. Data were collected from multiple brain regions and multiple time points after social challenge exposure, achieving anatomical and temporal resolution substantially greater than previous work. We developed statistically rigorous analyses equipped to find homologous functional groups among these species at the levels of individual genes, functional and coexpressed gene modules, and transcription factor subnetworks. We identified six orthogroups involved in response to social challenge, including groups represented by mouse genes Npas4 and Nr4a1, as well as common modulation of systems such as transcriptional regulators, ion channels, G-protein-coupled receptors and synaptic proteins. We also identified conserved coexpression modules enriched for mitochondrial fatty acid metabolism and heat shock that constitute the shared neurogenomic response. Our analysis suggests a toolkit wherein nuclear receptors, interacting with chaperones, induce transcriptional changes in mitochondrial activity, neural cytoarchitecture and synaptic transmission after social challenge. It shows systems-level mechanisms that have been repeatedly co-opted during evolution of analogous behaviors, thus advancing the genetic toolkit concept beyond individual genes.


News Coverage: Study finds parallels between unresponsive honey bees, autism in humans

Honey bees that consistently fail to respond to obvious social cues share something fundamental with autistic humans, researchers report in a new study. Genes most closely associated with autism spectrum disorders in humans are regulated differently in unresponsive honey bees than in their more responsive nest mates, the study found.

The findings, reported in the Proceedings of the National Academy of Sciences, appear to be unique to genes associated with autism and not to other behavioral disorders in humans. The study offers an early glimpse of the molecular heritage shared across the animal kingdom, the researchers say, and offers tantalizing clues about the evolution of social behavior.

Postdoctoral researcher Michael Saul, left, IGB director and entomology professor Gene Robinson and their colleagues found that genes that are closely associated with autism spectrum disorders in humans are regulated differently in the brains of socially unresponsive honey bees than in bees that behave more typically.
Postdoctoral researcher Michael Saul, left, IGB director and entomology professor Gene Robinson and their colleagues found that genes that are closely associated with autism spectrum disorders in humans are regulated differently in the brains of socially unresponsive honey bees than in bees that behave more typically.

“Some honey bees are more active than others, and some appear indifferent to intruders that threaten the hive. This, in itself, is not unusual,” said University of Illinois entomology professor Gene Robinson, who led the new analysis. “Honey bees take on different roles at different stages of their lifecycle, and not every bee can – or should – function as a guard,” he said.

But when postdoctoral researcher Hagai Shpigler observed that some of those same bees also were unmoved by the presence of a queen larva – a stimulus that typically spurs diligent action in nurse bees – it suggested something unusual was going on, said Robinson, who directs the Carl R. Woese Institute for Genomic Biology at the U. of I.

Continue Reading →

News Coverage: Brief interactions spur lasting waves of gene activity in the brain

A five-minute encounter with an outsider spurs a cascade of changes in gene activity in the brain that can last for hours, researchers report in a study of stickleback fish.

The research, described in the journal PLOS Genetics, is one of three recent studies  – the others conducted in honey bees and mice – to see waves of changes in gene expression in the brain 30 minutes to two hours after contact with an intruder.

University of Illinois animal biology professor Alison Bell, graduate student Syed Abbas Bukhari and their colleagues tracked changes in gene expression in the stickleback brain after the fish encountered an intruder.

“We are discovering that social interactions are extremely potent; they provoke big changes in gene expression in the brain,” said University of Illinois animal biology professor Alison Bell, who studies behavior in three-spined stickleback fish. “These very subtle social interactions are getting under the skin and becoming embedded in the brain. Studies like ours are beginning to show how that actually works.” Bell is a member of the IGB’s Gene Networks in Neural & Developmental Plasticity research theme, which supported this research.

Continue Reading →

Temporal dynamics of neurogenomic plasticity in response to social interactions in male threespined sticklebacks

Syed Abbas Bukhari, Michael C. Saul, Christopher H. Seward, Huimin Zhang, Miles Bensky, Noelle James, Sihai Dave Zhao, Sriram Chandrasekaran, Lisa Stubbs, Alison M. Bell

Animals exhibit dramatic immediate behavioral plasticity in response to social interactions, and brief social interactions can shape the future social landscape. However, the molecular mechanisms contributing to behavioral plasticity are unclear. Here, we show that the genome dynamically responds to social interactions with multiple waves of transcription associated with distinct molecular functions in the brain of male threespined sticklebacks, a species famous for its behavioral repertoire and evolution. Some biological functions (e.g., hormone activity) peaked soon after a brief territorial challenge and then declined, while others (e.g., immune response) peaked hours afterwards. We identify transcription factors that are predicted to coordinate waves of transcription associated with different components of behavioral plasticity. Next, using H3K27Ac as a marker of chromatin accessibility, we show that a brief territorial intrusion was sufficient to cause rapid and dramatic changes in the epigenome. Finally, we integrate the time course brain gene expression data with a transcriptional regulatory network, and link gene expression to changes in chromatin accessibility. This study reveals rapid and dramatic epigenomic plasticity in response to a brief, highly consequential social interaction.


World of Genomics brings Stubbs lab and IGB research to Chicago

From May 18th to 20th in Chicago, over 15,000 visitors experienced the World of Genomics at the Field Museum of Natural History, a three-day event presented by the Carl R. Woese Institute for Genomic Biology. A large, blue-lit funnel representing the tree of life dominated the space; beneath it, the world’s smallest sequencer read out the genomes of never-before-sequenced organisms currently studied at the IGB.

With six learning stations distributed across Stanley Field Hall, the main floor of the museum where famous T. rex  Sue is displayed, World of Genomics represented the full scope of IGB research in health, technology, and the environment, with hands on activities and exhibits for all ages.

“In all of the outreach events I’ve been a part of, I’ve never experienced such an engaged audience that asked so many excellent, relevant questions about our research,” said Beryl Jones, one of the over 60 volunteers from the IGB who staffed the event. “World of Genomics was truly one of the most rewarding experiences of my PhD, and I feel honored to have been a part of an event that reached so many people.”

Continue Reading →