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Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):E1577-86. doi: 10.1073/pnas.1502182112. Epub 2015 Mar 13.

Spatial proximity of homologous alleles and long noncoding RNAs regulate a switch in allelic gene expression.

Author information

1
Institute of Molecular Biology and Biotechnology-Foundation for Research and Technology Hellas, GR70013 Heraklion, Greece; Department of Biology, University of Crete, GR70013 Heraklion, Greece;
2
Institute of Molecular Biology and Biotechnology-Foundation for Research and Technology Hellas, GR70013 Heraklion, Greece;
3
Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089; and.
4
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.
5
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.

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.

KEYWORDS:

Tnfα; homologous spatial proximity; lncRNAs; macrophages

PMID:
25770217
PMCID:
PMC4386343
DOI:
10.1073/pnas.1502182112
[Indexed for MEDLINE]
Free PMC Article

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