title: Spatial proximity of homologous alleles and long noncoding RNAs regulate a switch in allelic gene expression.
abstract: Physiological processes rely on the regulation of total mRNA levels in a cell. In diploid organisms, the transcriptional activation of one or both alleles of a gene may involve trans-allelic interactions that provide a tight spatial and temporal level of gene expression regulation. The mechanisms underlying such interactions still remain poorly understood. Here, we demonstrate that lipopolysaccharide stimulation of murine macrophages rapidly resulted in the actin-mediated and transient homologous spatial proximity of Tnfα alleles, which was necessary for the mono- to biallelic switch in gene expression. We identified two new complementary long noncoding RNAs transcribed from the TNFα locus and showed that their knockdown had opposite effects in Tnfα spatial proximity and allelic expression. Moreover, the observed spatial proximity of Tnfα alleles depended on pyruvate kinase muscle isoform 2 (PKM2) and T-helper-inducing POZ-Krüppel-like factor (ThPOK). This study suggests a role for lncRNAs in the regulation of somatic homologous spatial proximity and allelic expression control necessary for fine-tuning mammalian immune responses.
authors.affiliation: Institute of Molecular Biology and Biotechnology-Foundation for Research and Technology Hellas, GR70013 Heraklion, Greece; Department of Biology, University of Crete, GR70013 Heraklion, Greece;
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Stratigi
authors.affiliation: Institute of Molecular Biology and Biotechnology-Foundation for Research and Technology Hellas, GR70013 Heraklion, Greece;
authors.forename: Manouela
authors.initials: M
authors.lastname: Kapsetaki
authors.affiliation: Institute of Molecular Biology and Biotechnology-Foundation for Research and Technology Hellas, GR70013 Heraklion, Greece;
authors.forename: Michalis
authors.initials: M
authors.lastname: Aivaliotis
authors.affiliation: Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089; and.
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
authors.affiliation: Department of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520 spiliana@imbb.forth.gr richard.flavell@yale.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Institute of Molecular Biology and Biotechnology-Foundation for Research and Technology Hellas, GR70013 Heraklion, Greece; Department of Biology, University of Crete, GR70013 Heraklion, Greece; spiliana@imbb.forth.gr richard.flavell@yale.edu.
authors.forename: Charalampos G
authors.initials: CG
authors.lastname: Spilianakis
mesh_terms: D000483:Alleles; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017404:In Situ Hybridization, Fluorescence; D008070:Lipopolysaccharides / Q000737:chemistry; D008233:Lymphotoxin-alpha / Q000235:genetics*; D053308:Lymphotoxin-beta / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062085:RNA, Long Noncoding; D013963:Thyroid Hormones / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D062085:RNA, Long Noncoding; D013963:Thyroid Hormones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000097810:Thyroid Hormone-Binding Proteins; C497211:Zbtb7b protein, mouse
keywords: Tnfα; homologous spatial proximity; lncRNAs; macrophages