The human lncRNA GOMAFU suppresses neuronal interferon response pathways affected in neuropsychiatric diseases.

Long noncoding RNAs (lncRNAs) play multifaceted roles in regulating brain gene networks. LncRNA abnormalities are thought to underlie the complex etiology of numerous neuropsychiatric disorders. One example is the human lncRNA gene GOMAFU, which is found dysregulated in schizophrenia (SCZ) postmortem brains and harbors genetic variants that contribute to the risk of SCZ. However, transcriptome-wide biological pathways regulated by GOMAFU have not been determined. How GOMAFU dysregulation contributes to SCZ pathogenesis remains elusive. Here we report that GOMAFU is a novel suppressor of human neuronal interferon (IFN) response pathways that are hyperactive in the postmortem SCZ brains. We analyzed recently released transcriptomic profiling datasets in clinically relevant brain areas derived from multiple SCZ cohorts and found brain region-specific dysregulation of GOMAFU. Using CRISPR-Cas9 to delete the GOMAFU promoter in a human neural progenitor cell model, we identified transcriptomic alterations caused by GOMAFU deficiency in pathways commonly affected in postmortem brains of SCZ and autism spectrum disorder (ASD), with the most striking effects on upregulation of numerous genes underlying IFN signaling. In addition, expression levels of GOMAFU target genes in the IFN pathway are differentially affected in SCZ brain regions and negatively associated with GOMAFU alterations. Furthermore, acute exposure to IFN-γ causes a rapid decline of GOMAFU and activation of a subclass of GOMAFU targets in stress and immune response pathways that are affected in SCZ brains, which form a highly interactive molecular network. Together, our studies unveiled the first evidence of lncRNA-governed neuronal response pathways to IFN challenge and suggest that GOMAFU dysregulation may mediate environmental risks and contribute to etiological neuroinflammatory responses by brain neurons of neuropsychiatric diseases.

MIAT, a potent CVD-promoting lncRNA.

The initial identification of long non-coding RNA myocardial infarction associated transcript (MIAT) as a genetic risk factor of myocardial infarction has made this lncRNA (designated as lncR-MIAT here) a focus of intensive studies worldwide. Emerging evidence supports that lncR-MIAT is susceptible in its expression to multiple deleterious factors like angiotensin II, isoproterenol, hypoxia, and infection and is anomaly overexpressed in serum, plasma, blood cells and myocardial tissues under a variety of cardiovascular conditions including myocardial infarction, cardiac hypertrophy, diabetic cardiomyopathy, dilated cardiomyopathy, sepsis cardiomyopathy, atrial fibrillation and microvascular dysfunction. Experimental results consistently demonstrated that upregulation of lncR-MIAT plays active roles in the pathological processes of the cardiovascular system and knockdown of this lncRNA effectively ameliorates the adverse conditions. The available data revealed that lncR-MIAT acts through multiple mechanisms such as competitive endogenous RNA, natural antisense RNA and RNA/protein interactions. Moreover, the functional domains of lncR-MIAT accounting for certain specific cellular functions of the full-length transcript have been identified and characterized. These insights will not only tremendously advance our understanding of lncRNA biology and pathophysiology, but also offer good opportunities for more innovative and precise design of agents that have the potential to be developed into new drugs for better therapy of cardiovascular diseases (CVDs) in the future. Herein, we provide an overview of lncR-MIAT, focusing on its roles in cardiovascular diseases, underline the unique cellular/molecular mechanisms for its actions, and speculate the perspectives about the translational studies on the potential diagnostic and therapeutic applications of lncR-MIAT.

The Long Non-Coding RNA GOMAFU in Schizophrenia: Function, Disease Risk, and Beyond.

Neuropsychiatric diseases are among the most common brain developmental disorders, represented by schizophrenia (SZ). The complex multifactorial etiology of SZ remains poorly understood, which reflects genetic vulnerabilities and environmental risks that affect numerous genes and biological pathways. Besides the dysregulation of protein-coding genes, recent discoveries demonstrate that abnormalities associated with non-coding RNAs, including microRNAs and long non-coding RNAs (lncRNAs), also contribute to the pathogenesis of SZ. lncRNAs are an actively evolving family of non-coding RNAs that harbor greater than 200 nucleotides but do not encode for proteins. In general, lncRNA genes are poorly conserved. The large number of lncRNAs specifically expressed in the human brain, together with the genetic alterations and dysregulation of lncRNA genes in the SZ brain, suggests a critical role in normal cognitive function and the pathogenesis of neuropsychiatric diseases. A particular lncRNA of interest is GOMAFU, also known as MIAT and RNCR2. Growing evidence suggests the function of GOMAFU in governing neuronal development and its potential roles as a risk factor and biomarker for SZ, which will be reviewed in this article. Moreover, we discuss the potential mechanisms through which GOMAFU regulates molecular pathways, including its subcellular localization and interaction with RNA-binding proteins, and how interruption to GOMAFU pathways may contribute to the pathogenesis of SZ.

Berberine ameliorates obesity-induced chronic inflammation through suppression of ER stress and promotion of macrophage M2 polarization at least partly via downregulating lncRNA Gomafu.

BACKGROUND: Berberine has been established as a potential drug for inflammation and metabolic disorder. Here, we aimed to explore the effects and the underlying mechanisms of berberine on obesity-induced chronic inflammation. METHODS: Mice were fed with high-fat diet to induce obesity. Inflammation in adipocytes were induced with treatment of free fatty acids. The expression of IL-4, CD206, ARG1 and other markers were used to identify M1 and M2 polarization. The expression of GPR78 and CHOP were used to evaluate endoplasmic reticulum stress. H&E staining was used to reveal the adipose tissue macrophage and adipocytes enlargement. RESULTS: Berberine treatment attenuated endoplasmic reticulum stress and inflammation in obese mice and free fatty acids-treated adipocytes. Overexpression of lncRNA Gomafu partially blocked the protective effects of berberine in free fatty acids-treated adipocytes by increasing endoplasmic reticulum stress. Moreover, Gomafu overexpression partly reversed berberine-induced enhancement of M2 polarization in macrophages. Finally, Gomafu overexpression induced ER stress and inflammation in mice, which were improved by berberine administration. CONCLUSIONS: Berberine improves obesity-induced chronic inflammation by alleviating endoplasmic reticulum stress and consequently promoting macrophage M2 polarization. And these protective effects were mediated at least partly by the suppression of lncRNA Gomafu.

Knocking Down Long Noncoding RNAs Using Antisense Oligonucleotide Gapmers.

Long noncoding RNAs (lncRNAs) are a class of RNA with 200 nucleotides or longer that are not translated into protein. lncRNAs are highly abundant; a study estimates that at least four times more lncRNAs are typically present than coding RNAs in humans. However, function of more than 95% of human lncRNAs are still unknown. Synthetic antisense oligonucleotides called gapmers are powerful tools for lncRNA loss-of-function studies. Gapmers contain a central DNA part, which activates RNase H-mediated RNA degradation, flanked by modified oligonucleotides, such as 2'-O-methyl RNA (2'OMe), 2'-O-methoxyethyl RNA (2'MOE), constrained ethyl nucleosides (cEt), and locked nucleic acids (LNAs). In contrast to siRNA or RNAi-based methods, antisense oligonucleotide gapmer-based knockdown is often more effective against nuclear-localized lncRNA targets, since RNase H is mainly localized in nuclei. As such, gapmers are also potentially a powerful tool for therapeutics targeting lncRNAs in various diseases, including cancer, cardiovascular diseases, lung fibrosis, and neurological/neuromuscular diseases. This chapter will discuss the development and applications of gapmers for lncRNA loss-of-function studies and tips to design effective antisense oligonucleotides.

LncRNA MIAT: Myocardial infarction associated and more.

Non-coding RNAs are emerging as regulatory RNAs that participate in the regulation of gene expression and play vital roles in various biological and pathological processes. Long non-coding (lncRNA) is a novel class of non-coding RNAs that regulates gene expression by binding to chromatin regulators and interfering RNAs to affect cellular response. Myocardial infarction associated transcript (MIAT) is identified as lncRNAs, which is involved in various diseases, pathological and physiological processes, such as myocardial infarction, diabetic retinopathy, paranoid schizophrenia, microvascular dysfunction and formation of nuclear bodies, and neurogenic commitment. Here we review the growing understanding and potential utilization of MIAT.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.