title: Transcriptional regulatory dynamics drive coordinated metabolic and neural response to social challenge in mice.
abstract: Agonistic encounters are powerful effectors of future behavior, and the ability to learn from this type of social challenge is an essential adaptive trait. We recently identified a conserved transcriptional program defining the response to social challenge across animal species, highly enriched in transcription factor (TF), energy metabolism, and developmental signaling genes. To understand the trajectory of this program and to uncover the most important regulatory influences controlling this response, we integrated gene expression data with the chromatin landscape in the hypothalamus, frontal cortex, and amygdala of socially challenged mice over time. The expression data revealed a complex spatiotemporal patterning of events starting with neural signaling molecules in the frontal cortex and ending in the modulation of developmental factors in the amygdala and hypothalamus, underpinned by a systems-wide shift in expression of energy metabolism-related genes. The transcriptional signals were correlated with significant shifts in chromatin accessibility and a network of challenge-associated TFs. Among these, the conserved metabolic and developmental regulator ESRRA was highlighted for an especially early and important regulatory role. Cell-type deconvolution analysis attributed the differential metabolic and developmental signals in this social context primarily to oligodendrocytes and neurons, respectively, and we show that ESRRA is expressed in both cell types. Localizing ESRRA binding sites in cortical chromatin, we show that this nuclear receptor binds both differentially expressed energy-related and neurodevelopmental TF genes. These data link metabolic and neurodevelopmental signaling to social challenge, and identify key regulatory drivers of this process with unprecedented tissue and temporal resolution.
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Saul
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.|Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Seward
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.|Illinois Informatics Institute, Urbana, Illinois 61801, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Troy
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.|Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.|Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Sloofman
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.|Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Lu
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.|Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Weisner
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.|Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Caetano-Anolles
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.|Department of Statistics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Sihai Dave
authors.initials: SD
authors.lastname: Zhao
authors.affiliation: Harvard Society of Fellows, Harvard University, Cambridge, Massachusetts 02138, USA.|Faculty of Arts and Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Chandrasekaran
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.|Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.|Department of Computer Science.|Department of Entomology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.|Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.|Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Stubbs
mesh_terms: D000378:Agonistic Behavior; D000679:Amygdala / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002843:Chromatin / Q000378:metabolism* / Q000648:ultrastructure; D004734:Energy Metabolism / Q000235:genetics; D005625:Frontal Lobe / Q000378:metabolism / Q000503:physiopathology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D007031:Hypothalamus / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D002843:Chromatin; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor