title: Orthogonal control of expression mean and variance by epigenetic features at different genomic loci.
abstract: While gene expression noise has been shown to drive dramatic phenotypic variations, the molecular basis for this variability in mammalian systems is not well understood. Gene expression has been shown to be regulated by promoter architecture and the associated chromatin environment. However, the exact contribution of these two factors in regulating expression noise has not been explored. Using a dual-reporter lentiviral model system, we deconvolved the influence of the promoter sequence to systematically study the contribution of the chromatin environment at different genomic locations in regulating expression noise. By integrating a large-scale analysis to quantify mRNA levels by smFISH and protein levels by flow cytometry in single cells, we found that mean expression and noise are uncorrelated across genomic locations. Furthermore, we showed that this independence could be explained by the orthogonal control of mean expression by the transcript burst size and noise by the burst frequency. Finally, we showed that genomic locations displaying higher expression noise are associated with more repressed chromatin, thereby indicating the contribution of the chromatin environment in regulating expression noise.
authors.affiliation: Department of Chemical and Biomolecular Engineering and the Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA Institute for Quantitative Biosciences, University of California, Berkeley, CA, USA.
authors.forename: Siddharth S
authors.initials: SS
authors.lastname: Dey
authors.affiliation: Department of Bioengineering, University of California, Berkeley, CA, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Foley
authors.affiliation: Department of Plant and Microbial Biology, University of California, Berkeley, CA, USA.
authors.forename: Prajit
authors.initials: P
authors.lastname: Limsirichai
authors.affiliation: Department of Chemical and Biomolecular Engineering and the Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA Institute for Quantitative Biosciences, University of California, Berkeley, CA, USA Department of Bioengineering, University of California, Berkeley, CA, USA Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA schaffer@berkeley.edu aparkin@lbl.gov.
authors.forename: David V
authors.initials: DV
authors.lastname: Schaffer
authors.affiliation: Department of Bioengineering, University of California, Berkeley, CA, USA Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA Virtual Institute of Microbial Stress and Survival, Lawrence Berkeley National Laboratory, Berkeley, CA, USA DOE, Joint BioEnergy Institute Lawrence Berkeley National Laboratory, Berkeley, CA, USA schaffer@berkeley.edu aparkin@lbl.gov.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Arkin
mesh_terms: D002843:Chromatin / Q000378:metabolism; D044127:Epigenesis, Genetic; D023281:Genomics; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D019169:Jurkat Cells; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000032:analysis*; D012333:RNA, Messenger / Q000032:analysis*
chemical_list: D002843:Chromatin; D011506:Proteins; D012333:RNA, Messenger
keywords: chromatin environment; gene expression noise; single‐cell biology; single‐molecule RNA FISH