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Long Noncoding RNA-Directed Epigenetic Regulation of Gene Expression Is Associated With Anxiety-like Behavior in Mice.

ABSTRACT: RNA-directed regulation of epigenetic processes has recently emerged as an important feature of mammalian differentiation and development. Perturbation of this regulatory system in the brain may contribute to the development of neuropsychiatric disorders.RNA sequencing was used to identify changes in the experience-dependent expression of long noncoding RNAs (lncRNAs) within the medial prefrontal cortex of adult mice. Transcripts were validated by real-time quantitative polymerase chain reaction and a candidate lncRNA, Gomafu, was selected for further investigation. The functional role of this schizophrenia-related lncRNA was explored in vivo by antisense oligonucleotide-mediated gene knockdown in the medial prefrontal cortex, followed by behavioral training and assessment of fear-related anxiety. Long noncoding RNA-directed epigenetic regulation of gene expression was investigated by chromatin and RNA immunoprecipitation assays.RNA sequencing analysis revealed changes in the expression of a significant number of genes related to neural plasticity and stress, as well as the dynamic regulation of lncRNAs. In particular, we detected a significant downregulation of Gomafu lncRNA. Our results revealed that Gomafu plays a role in mediating anxiety-like behavior and suggest that this may occur through an interaction with a key member of the polycomb repressive complex 1, BMI1, which regulates the expression of the schizophrenia-related gene beta crystallin (Crybb1). We also demonstrated a novel role for Crybb1 in mediating fear-induced anxiety-like behavior.Experience-dependent expression of lncRNAs plays an important role in the epigenetic regulation of adaptive behavior, and the perturbation of Gomafu may be related to anxiety and the development of neuropsychiatric disorders.

SUBMITTER: Spadaro PA

PROVIDER: S-EPMC4532653 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Long Noncoding RNA-Directed Epigenetic Regulation of Gene Expression Is Associated With Anxiety-like Behavior in Mice.

Spadaro Paola A PA Flavell Charlotte R CR Widagdo Jocelyn J Ratnu Vikram S VS Troup Michael M Ragan Chikako C Mattick John S JS Bredy Timothy W TW

Biological psychiatry 20150211 12

<h4>Background</h4>RNA-directed regulation of epigenetic processes has recently emerged as an important feature of mammalian differentiation and development. Perturbation of this regulatory system in the brain may contribute to the development of neuropsychiatric disorders.<h4>Methods</h4>RNA sequencing was used to identify changes in the experience-dependent expression of long noncoding RNAs (lncRNAs) within the medial prefrontal cortex of adult mice. Transcripts were validated by real-time qua ...[more]

PMID: 25792222

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Project description:A major challenge in finding a cure for HIV-1/AIDS is the difficulty in identifying and eradicating persistent reservoirs of replication-competent provirus. Long noncoding RNAs (lncRNAs, >200 nucleotides) are increasingly recognized to play important roles in pathophysiology. Here, we report the first genome-wide expression analysis of lncRNAs in HIV-1-infected primary monocyte-derived macrophages (MDMs). We identified an lncRNA, which we named HIV-1-enhanced lncRNA (HEAL), that is upregulated by HIV-1 infection of MDMs, microglia, and T lymphocytes. Peripheral blood mononuclear cells of HIV-1-infected individuals show elevated levels of HEAL Importantly, HEAL is a broad enhancer of multiple HIV-1 strains because depletion of HEAL inhibited X4, R5, and dual-tropic HIV replications and the inhibition was rescued by HEAL overexpression. HEAL forms a complex with the RNA-binding protein FUS, which facilitates HIV replication through at least two mechanisms: (i) HEAL-FUS complex binds the HIV promoter and enhances recruitment of the histone acetyltransferase p300, which positively regulates HIV transcription by increasing histone H3K27 acetylation and P-TEFb enrichment on the HIV promoter, and (ii) HEAL-FUS complex is enriched at the promoter of the cyclin-dependent kinase 2 gene, CDK2, to enhance CDK2 expression. Notably, HEAL knockdown and knockout mediated by RNA interference (RNAi) and CRISPR-Cas9, respectively, prevent HIV-1 recrudescence in T cells and microglia upon cessation of azidothymidine treatment in vitro Our results suggest that silencing of HEAL or perturbation of the HEAL-FUS ribonucleoprotein complex could provide a new epigenetic silencing strategy to eradicate viral reservoirs and effect a cure for HIV-1/AIDS.IMPORTANCE Despite our increased understanding of the functions of lncRNAs, their potential to develop HIV/AIDS cure strategies remains unexplored. A genome-wide analysis of lncRNAs in HIV-1-infected primary monocyte-derived macrophages (MDMs) was performed, and 1,145 differentially expressed lncRNAs were identified. An lncRNA named HIV-1-enhanced lncRNA (HEAL) is upregulated by HIV-1 infection and promotes HIV replication in T cells and macrophages. HEAL forms a complex with the RNA-binding protein FUS to enhance transcriptional coactivator p300 recruitment to the HIV promoter. Furthermore, HEAL knockdown and knockout prevent HIV-1 recrudescence in T cells and microglia upon cessation of azidothymidine treatment, suggesting HEAL as a potential therapeutic target to cure HIV-1/AIDS.

Project description:BackgroundHigh levels of fetal hemoglobin (HbF) may alleviate clinical symptoms in patients with β-thalassemia. A previous study showed that the long noncoding RNA NR_120526 (lncRNA NR_120526) might be involved in regulating HbF levels (HBG1/2 gene expression). However, the function and mechanism by which NR_120526 regulates HbF expression remains unknown. Here, we investigated the effect of NR_120526 on HbF and its mechanism so as to provide an experimental basis for treating patients with β-thalassemia.MethodsChromatin isolation by RNA purification-mass spectrometry (ChIRP-MS) assay, database query, and bioinformatics analysis were performed to explore the proteins that specifically bind to NR_120526 and their interactions. Chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-seq) were used to determine whether NR_120526 directly regulates the expression of HBG1/2. The NR_120526 gene was knocked out (KO) using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology in K562 cells. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the messenger RNA (mRNA) and protein expressions of HBG1/2, ribosomal protein S6 kinase B1 (RPS6KB1, S6K), and Ras homologous family member A (RhoA), respectively.ResultsWe found that NR_120526 interacts with ILF2, ILF3, and S6K. However, ILF2/ILF3 bound to NR_120526 did not interact with HBG1/2, suggesting that NR_120526 may regulate HBG1/2 expression indirectly. The qRT-PCR results showed no statistical difference in the mRNA expression levels of HBG1/2, S6K, and RhoA between the NR_120526-KO group and negative control (NC) group (P>0.05). However, Western blot results showed a significant increase in the protein levels of HBG1/2, S6K, and RhoA in the KO group (P<0.05). It was found that NR_120526 inhibited S6K, thereby downregulating RhoA and leading to decreased HBG1/2 expression.ConclusionsLncRNA NR_120526 negatively regulates the expression of HBG1/2 through S6K. These new findings provide mechanistic insights into the regulation of HbF and offer potential therapeutic targets for precision medicine in patients with β-thalassemia.

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Long Noncoding RNA-Directed Epigenetic Regulation of Gene Expression Is Associated With Anxiety-like Behavior in Mice.

Publications

Long Noncoding RNA-Directed Epigenetic Regulation of Gene Expression Is Associated With Anxiety-like Behavior in Mice.

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