title: Inputs drive cell phenotype variability.
abstract: What is the significance of the extensive variability observed in individual members of a single-cell phenotype? This question is particularly relevant to the highly differentiated organization of the brain. In this study, for the first time, we analyze the in vivo variability within a neuronal phenotype in terms of input type. We developed a large-scale gene-expression data set from several hundred single brainstem neurons selected on the basis of their specific synaptic input types. The results show a surprising organizational structure in which neuronal variability aligned with input type along a continuum of sub-phenotypes and corresponding gene regulatory modules. Correlations between these regulatory modules and specific cellular states were stratified by synaptic input type. Moreover, we found that the phenotype gradient and correlated regulatory modules were maintained across subjects. As these specific cellular states are a function of the inputs received, the stability of these states represents "attractor"-like states along a dynamic landscape that is influenced and shaped by inputs, enabling distinct state-dependent functional responses. We interpret the phenotype gradient as arising from analog tuning of underlying regulatory networks driven by distinct inputs to individual cells. Our results change the way we understand how a phenotypic population supports robust biological function by integrating the environmental experience of individual cells. Our results provide an explanation of the functional significance of the pervasive variability observed within a cell type and are broadly applicable to understanding the relationship between cellular input history and cell phenotype within all tissues.
authors.affiliation: Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA; Department of Chemical and Biochemical Engineering, University of Delaware, Newark, Delaware 19716, USA;
authors.forename: James
authors.initials: J
authors.lastname: Park
authors.affiliation: Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA;
authors.forename: Anthony
authors.initials: A
authors.lastname: Brureau
authors.affiliation: Department of Pediatrics, Washington University Saint Louis, Saint Louis, Missouri 63130, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Kernan
authors.affiliation: Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA;
authors.forename: Alexandria
authors.initials: A
authors.lastname: Starks
authors.affiliation: Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA;
authors.forename: Sonali
authors.initials: S
authors.lastname: Gulati
authors.affiliation: Department of Chemical and Biochemical Engineering, University of Delaware, Newark, Delaware 19716, USA;
authors.forename: Babatunde
authors.initials: B
authors.lastname: Ogunnaike
authors.affiliation: Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA; Department of Chemical and Biochemical Engineering, University of Delaware, Newark, Delaware 19716, USA;
authors.forename: James
authors.initials: J
authors.lastname: Schwaber
authors.affiliation: Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA; Department of Chemical and Biochemical Engineering, University of Delaware, Newark, Delaware 19716, USA;
authors.forename: Rajanikanth
authors.initials: R
authors.lastname: Vadigepalli
mesh_terms: D000818:Animals; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017552:Solitary Nucleus / Q000166:cytology; D009435:Synaptic Transmission; D014158:Transcription, Genetic; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D014446:Tyrosine 3-Monooxygenase