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

Stratigi, Kalliopi; Kapsetaki, M.; Aivaliotis, Michalis; Town, Terrence; Flavell, Richard A.; Spilianakis, Charalampos G.

doi:10.1073/pnas.1502182112

Cited by 27 publications

(37 citation statements)

References 55 publications

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“…Interestingly, mammalian pairing is often associated with critical cellular processes, including DNA repair and V(D)J recombination, in addition to transcriptional regulation during X-inactivation, imprinting, and cell fate establishment [45, 46, 48, 49, 66-77]. Homologous association of pericentromeric regions has also been documented for human chromosomes 1, 7, 8, 10, and 17 [78-81].…”

Section: A New Model For Homolog Positioning In Humansmentioning

confidence: 99%

Pairing and anti-pairing: a balancing act in the diploid genome

Joyce

Erceg

2016

Current Opinion in Genetics & Development

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The presence of maternal and paternal homologs appears to be much more than just a doubling of genetic material. We know this because genomes have evolved elaborate mechanisms that permit homologous regions to sense and then respond to each other. One way in which homologs communicate is to come into contact and, in fact, Dipteran insects such as Drosophila excel at this task, aligning all pairs of maternal and paternal chromosomes, end-to-end, in essentially all somatic tissues throughout development. Here, we reexamine the widely held tenet that extensive somatic pairing of homologous sequences cannot occur in mammals and suggest, instead, that pairing may be a widespread and significant potential that has gone unnoticed in mammals because they expend considerable effort to prevent it. We then extend this discussion to interchromosomal interactions, in general, and speculate about the potential of nuclear organization and pairing to impact inheritance.

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Section: A New Model For Homolog Positioning In Humansmentioning

confidence: 99%

Pairing and anti-pairing: a balancing act in the diploid genome

Joyce

Erceg

2016

Current Opinion in Genetics & Development

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“…The Tnfα gene locus is located on mouse chromosome 17 and encompasses three genes involved in the regulation of the immune system, namely the lymphotoxin alpha gene ( Ltα ), the Tumor necrosis factor alpha gene ( Tnfα ) and the lymphotoxin beta gene ( Ltβ ) ( Fig 1A ). We have previously shown that the long non-coding RNA SeT is also expressed from the Tnfα locus and has an impact on the regulation of the homologous pairing of Tnfα alleles and ultimately the regulation of the allelic expression profile of the Tnfα gene [ 54 ]. In this study, we have targeted the Tnfα locus ( Fig 1B ) and created two mice with either constitutive deletion of the regulatory elements of the SeT lncRNA or tissue specific deletion of the same sequences in bone marrow derived macrophages ( Fig 1C ).…”

Section: Resultsmentioning

confidence: 99%

“…It is thus evident that a tightly regulated balance of TNFα levels is of critical importance. Transcriptional activation and expression of Tnfα downstream of the NF-κB signaling pathway is cell type and stimulus dependent and regulated in a spatiotemporal manner [ 53 , 54 ]. Tnfα monoallelic expression downstream of TLR4 activation in murine macrophages precedes the homologous association of the two alleles followed by biallelic Tnfα expression early upon the initiation of the inflammatory response [ 54 ].…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that the 12.34 kb SeT lncRNA, which is encoded by the Tnfα gene locus, is significantly upregulated in LPS-induced murine macrophages and transcribed in a Tnfα -sense orientation. SeT lncRNA is involved in the regulation of the spatiotemporal expression of the Tnfα gene affecting its allelic expression profile [ 54 ]. Although crucial for the fine-tuning of immune responses, the mechanism by which the spatiotemporal regulation of Tnfα expression is effectuated, by means of homologous pairing and mono- to bi-allelic switch in transcription, is not fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Long non-coding RNA SeT and miR-155 regulate the Tnfα gene allelic expression profile

et al. 2017

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It is becoming increasingly appreciated that the non-coding genome may have a great impact on the regulation of chromatin structure and gene expression. The innate immune response can be mediated upon lipopolysaccharide stimulation of macrophages which leads to immediate transcriptional activation of early responsive genes including tumor necrosis factor alpha (Tnfα). The functional role of non-coding RNAs, such as lncRNAs and microRNAs, on the transcriptional activation of proinflammatory genes and the subsequent regulation of the innate immune response is still lacking mechanistic insights. In this study we wanted to unravel the functional role of the lncRNA SeT, which is encoded from the murine Tnfα gene locus, and miR-155 on the transcriptional regulation of the Tnfα gene. We utilized genetically modified mice harboring either a deletion of the SeT promoter elements or the mature miR-155 and studied the response of macrophages to lipopolysaccharide (LPS) stimulation. We found that decreased expression of the lncRNA SeT in murine primary macrophages resulted in increased mortality of mice challenged with LPS, which was corroborated by increased Tnfα steady state mRNA levels and a higher frequency of biallelically expressing macrophages. On the contrary, miR-155 deletion resulted in reduced Tnfα mRNA levels supported by a lower frequency of biallelically expressing macrophages upon stimulation with LPS. In both cases, in the absence of either lncRNA SeT or miR-155 we observed a deregulation of the Tnfα allele homologous pairing, previously shown to regulate the switch from mono- to bi-allelic gene expression. Although lncRNA SeT was not found to be a direct target of miR-155 its stability was increased upon miR-155 deletion. This study suggests a role of the non-coding genome in mediating Tnfα mRNA dosage control based on the regulation of homologous pairing of gene alleles and their subsequent biallelic expression.

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“…Similarly, lincRNA THRIL as a negative regulation of NF‐κB could interact with hnRNPL at the Tnfα gene and ensure the expression of TNF‐α in dosage control, but it down‐regulated in human macrophages after TLR2 activation . Encoded by the Tnfα loci, lncRNA SeT increased in LPS‐treated murine macrophage, with unstable Tnfα mRNA . The above lncRNAs are important to reduce TNFα expression in macrophages.…”

Section: Lncrnas Expression In Macrophage Polarization and Functionmentioning

confidence: 99%

Long non‐coding RNA expressed in macrophage co‐varies with the inflammatory phenotype during macrophage development and polarization

Xie

Wang

Tian

et al. 2019

J Cellular Molecular Medi

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Advances in microarray, RNA‐seq and omics techniques, thousands of long non‐coding RNAs (lncRNAs) with unknown functions have been discovered. LncRNAs have presented a diverse perspective on gene regulation in diverse biological processes, especially in human immune response. Macrophages participate in the whole phase of immune inflammatory response. They are able to shape their phenotype and arouse extensive functional activation after receiving physiological and pathological stimuli. Emerging studies indicated that lncRNAs participated in the gene regulatory network during complex biological processes of macrophage, including macrophage‐induced inflammatory responses. Here, we reviewed the existing knowledges of lncRNAs in the processes of macrophage development and polarization, and their roles in several different inflammatory diseases. Specifically, we focused on how lncRNAs function in macrophage, which might help to discover some potential therapeutic targets and diagnostic biomarkers.

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

Cited by 27 publications

References 55 publications

Pairing and anti-pairing: a balancing act in the diploid genome

Pairing and anti-pairing: a balancing act in the diploid genome

Long non-coding RNA SeT and miR-155 regulate the Tnfα gene allelic expression profile

Long non‐coding RNA expressed in macrophage co‐varies with the inflammatory phenotype during macrophage development and polarization

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