RESUMO
Long noncoding RNAs (lncRNAs) have emerged as critical regulators of gene expression, yet their contribution to immune regulation in humans remains poorly understood. Here, we report that the primate-specific lncRNA CHROMR is induced by influenza A virus and SARS-CoV-2 infection and coordinates the expression of interferon-stimulated genes (ISGs) that execute antiviral responses. CHROMR depletion in human macrophages reduces histone acetylation at regulatory regions of ISG loci and attenuates ISG expression in response to microbial stimuli. Mechanistically, we show that CHROMR sequesters the interferon regulatory factor (IRF)-2-dependent transcriptional corepressor IRF2BP2, thereby licensing IRF-dependent signaling and transcription of the ISG network. Consequently, CHROMR expression is essential to restrict viral infection of macrophages. Our findings identify CHROMR as a key arbitrator of antiviral innate immune signaling in humans.
Assuntos
COVID-19 , Proteínas de Ligação a DNA , Imunidade Inata , Vírus da Influenza A , Influenza Humana , RNA Longo não Codificante , SARS-CoV-2 , Fatores de Transcrição , COVID-19/genética , COVID-19/imunologia , Proteínas de Ligação a DNA/metabolismo , Humanos , Imunidade Inata/genética , Vírus da Influenza A/imunologia , Influenza Humana/genética , Influenza Humana/imunologia , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/fisiologia , SARS-CoV-2/imunologia , Fatores de Transcrição/metabolismoRESUMO
The human genome encodes thousands of long non-coding RNAs (lncRNAs), the majority of which are poorly conserved and uncharacterized. Here we identify a primate-specific lncRNA (CHROME), elevated in the plasma and atherosclerotic plaques of individuals with coronary artery disease, that regulates cellular and systemic cholesterol homeostasis. LncRNA CHROME expression is influenced by dietary and cellular cholesterol via the sterol-activated liver X receptor transcription factors, which control genes mediating responses to cholesterol overload. Using gain- and loss-of-function approaches, we show that CHROME promotes cholesterol efflux and HDL biogenesis by curbing the actions of a set of functionally related microRNAs that repress genes in those pathways. CHROME knockdown in human hepatocytes and macrophages increases levels of miR-27b, miR-33a, miR-33b and miR-128, thereby reducing expression of their overlapping target gene networks and associated biologic functions. In particular, cells lacking CHROME show reduced expression of ABCA1, which regulates cholesterol efflux and nascent HDL particle formation. Collectively, our findings identify CHROME as a central component of the non-coding RNA circuitry controlling cholesterol homeostasis in humans.
Assuntos
Colesterol/metabolismo , Homeostase , Primatas/genética , Primatas/metabolismo , RNA Longo não Codificante/genética , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos , Receptores X do Fígado/metabolismo , MicroRNAs/genéticaRESUMO
Non-coding RNAs, once considered "genomic junk", are now known to play central roles in the dynamic control of transcriptional and post-transcriptional gene expression. Long non-coding RNAs (lncRNAs) are an expansive class of transcripts broadly described as greater than 200 nucleotides in length. While most lncRNAs are species-specific, their lack of conservation does not imbue a lack of function. LncRNAs have been found to regulate numerous diverse biological functions, including those central to macrophage differentiation and activation. Through their ability to form RNA-DNA, RNA-protein and RNA-RNA interactions, lncRNAs have been implicated in the regulation of myeloid lineage determination, and innate and adaptive immune functions, among others. In this review, we discuss recent advances, current challenges and future opportunities in understanding the roles of lncRNAs in macrophage functions in homeostasis and disease.
Assuntos
Diferenciação Celular , Inflamação/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Regulação da Expressão Gênica , Homeostase , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/patologia , Fenótipo , RNA Longo não Codificante/genética , Transdução de SinaisRESUMO
PURPOSE OF REVIEW: Noncoding RNAs have emerged as important regulators of cellular and systemic lipid metabolism. In particular, the enigmatic class of long noncoding RNAs have been shown to play multifaceted roles in controlling transcriptional and posttranscriptional gene regulation. In this review, we discuss recent advances, current challenges and future opportunities in understanding the roles of lncRNAs in the regulation of lipid metabolism during health and disease. RECENT FINDINGS: Despite comprising the majority of the transcriptionally active regions of the human genome, lncRNA functions remain poorly understood, with fewer than 1% of human lncRNAs functionally characterized. Broadly defined as nonprotein coding transcripts greater than 200 nucleotides in length, lncRNAs execute their functions by forming RNA-DNA, RNA-protein, and RNA-RNA interactions that regulate gene expression through diverse mechanisms, including epigenetic remodeling of chromatin, transcriptional activation or repression, posttranscriptional regulation of mRNA, and modulation of protein activity. It is now recognized that in lipid metabolism, just as in other areas of biology, lncRNAs operate to regulate the expression of individual genes and gene networks at multiple different levels. SUMMARY: The complexity revealed by recent studies showing how lncRNAs can alter systemic and cell-type-specific cholesterol and triglyceride metabolism make it clear that we have entered a new frontier for discovery that is both daunting and exciting.
