期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：13
页码：E1577-E1586
DOI：10.1073/pnas.1502182112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceIn diploid organisms, trans-allelic interactions control gene expression, providing a tight spatial and temporal level of transcription regulation. Although homologous trans-allelic interactions are quite abundant in various organisms such as Drosophila, plants, and fungi, they have not been widely reported in mammals. This article demonstrates that such a trans-allelic association is evident in mammals and involves the homologous spatial proximity of Tnf alleles as a prerequisite for the biallelic expression of the Tnf gene. We believe the phenomenon we describe here provides mechanistic insights for the regulation of gene allelic expression and mRNA dosage control necessary for fine-tuning physiological processes in mammals. 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 Tnf alleles, which was necessary for the mono- to biallelic switch in gene expression. We identified two new complementary long noncoding RNAs transcribed from the TNF locus and showed that their knockdown had opposite effects in Tnf spatial proximity and allelic expression. Moreover, the observed spatial proximity of Tnf alleles depended on pyruvate kinase muscle isoform 2 (PKM2) and T-helper-inducing POZ-Kruppel-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.
