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LNCRHOXF1: a long noncoding RNA from the X-chromosome that suppresses viral response genes during development of the early human placenta

ABSTRACT: Long noncoding RNAs (lncRNAs) can regulate gene expression in a cell-specific fashion during development. Here we identify a novel lncRNA from the X-chromosome that we named lncRHOXF1 and which is abundantly expressed in trophectoderm and primitive endoderm cells of human blastocyst-stage embryos. LncRHOXF1 is a spliced and polyadenylated lncRNA about 1 kb in length, found in both the nuclear and cytoplasmic compartments of in vitro differentiated human trophectoderm progenitor cells. Gain of function experiments in human embryonic stem cells, which normally lack lncRHOXF1 RNA, revealed that lncRHOXF1 reduced proliferation and favored cellular differentiation. LncRHOXF1 knockdown using siRNAs in human trophectoderm progenitors increased expression of viral response genes, including type I interferon. Sendai virus infection of human trophectoderm progenitor cells increased lncRHOXF1 RNA levels and siRNA-mediated disruption of lncRHOXF1 during infection reduced the expression of viral response genes leading to higher virus replication. Thus, lncRHOXF1 RNA is the first example of a lncRNA that regulates the host response to viral infections in human placental progenitor cells, and we propose that it functions as a repressor of the viral response during early human development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81933 | GEO | 2016/05/27

SECONDARY ACCESSION(S): PRJNA323458

REPOSITORIES: GEO

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Project description:Paramyxoviruses are negative sense single-stranded RNA viruses that comprise many important human and animal pathogens, including human parainfluenza viruses. These viruses bud from the plasma membrane of infected cells after the viral ribonucleoprotein complex (vRNP) is transported from the cytoplasm to the cell membrane via Rab11a marked recycling endosomes. The viral proteins that are critical for mediating this important initial step in viral assembly are unknown. Here we use the model paramyxovirus, murine parainfluenza virus 1, or Sendai virus (SeV), to investigate the roles of viral proteins in Rab11a-driven virion assembly. We previously reported that infection with SeV containing high levels of copy-back defective viral genomes (DVGs) generates heterogenous populations of cells, with cells enriched in full-length virus producing viral particles containing standard or defective viral genomes, while cells enriched in DVGs did not, despite high levels of defective viral genome replication. Here we take advantage of this heterogenous cell phenotype to identify proteins that mediate interaction of vRNPs with Rab11a. We examine the role of matrix protein and nucleoprotein and determine that they are not sufficient to drive interaction of vRNPs and recycling endosomes. Then, using a combination of mass spectrometry and comparative protein abundance and localization in DVG- and FL-high cells, we identify viral polymerase complex components L and, specifically, its cofactor C proteins as interactors with Rab11a. We find that accumulation of these proteins within the cell is the defining feature that differentiates cells that proceed to viral egress from cells which remain in replication phases. Paramyxoviruses are a family of viruses that include a number of pathogens with significant burdens on human health. Particularly, human parainfluenza viruses are an important cause of pneumonia and bronchiolitis in children and do not have any vaccines or direct acting antivirals. These cytoplasmic replicating viruses bud from the plasma membrane and coopt cellular endosomal recycling pathways to traffic viral ribonucleoprotein complexes from the cytoplasm to the membrane of infected cells, yet the viral proteins required for viral engagement with the recycling endosome pathway is not known. Here we use the model paramyxovirus Sendai virus, or murine parainfluenza virus 1, to investigate the role of viral proteins in this initial step in viral assembly. We find that viral polymerase components large protein L and accessory C proteins are necessary for engagement with recycling endosomes. These findings are important in identifying viral targets for the development of antivirals.

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LNCRHOXF1: a long noncoding RNA from the X-chromosome that suppresses viral response genes during development of the early human placenta

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