Long Noncoding RNAs: A New Regulatory Code in Metabolic Control

Abstract

Long noncoding RNAs (lncRNAs) are emerging as an integral part of the regulatory information encoded in the genome. lncRNAs possess the unique capability to interact with nucleic acids and proteins, and exert discrete effects on numerous biological processes. Recent studies have delineated multiple lncRNA pathways that control metabolic tissue development and function. The expansion of the regulatory code that links nutrient and hormonal signals to tissue metabolism gives new insights into the genetic and pathogenic mechanisms underlying metabolic disease. This review discusses lncRNA biology with a focus on their role in the development, signaling, and function of key metabolic tissues.

Keywords: brown fat; energy metabolism; lncRNA; metabolic disease; signaling; transcription.

Figure 1. Different classes of lncRNAs

LncRNA genes can be classified into divergent, intronic, sense, antisense, and intergenic groups according to their location relative to the nearby protein-coding genes.

Figure 2. Regulation of thermogenic adipocyte differentiation and hepatic metabolism by lncRNAs

(A) Regulation of brown and beige adipogenesis by lncRNAs Blnc1 and lnc-BATE1. Blnc1 is highly induced during brown and beige adipocyte differentiation and physically interacts with EBF2 to promote thermogenic adipocyte differentiation through a feedforward regulatory loop. Lnc-BATE1 is enriched in brown fat, associates with hnRNP U, and is required for brown adipogenesis. (B) Regulation of hepatic metabolism by lncRNAs. LncLSTR regulates hydrolysis of plasma triglycerides by LPL through modulating ApoC2 expression in the liver. APOA1-AS is an antisense transcript that originates from and regulates the expression of genes within the APOA1/C3/A4/A5 cluster. HULC modulates lipid synthesis and tumor growth through its regulation of PPARα-ACSL1 expression. LncRNAs were shown in blue, microRNAs were shown in white, proteins were shown in grey. The abbreviations are as the following: Brown fat lncRNA 1 (Blnc1), Early B-cell factor 2 (EBF2), β-adrenergic receptor (βAR), Heterogeneous nuclear ribonucleoprotein (hnRNP) U, Liver-specific triglyceride regulator (lncLSTR), TAR DNA-binding protein 43 (TDP-43), Farnesoid X receptor (FXR), Lipoprotein lipase (LPL), Antisense transcript of ApoA1 (ApoA1-AS), Lysine-specific demethylase 1 (LSD1), Suppressor of zeste 12 homolog (SUZ12), Highly Up-regulated in Liver Cancer (HULC), Peroxisome proliferator-activated receptor α (PPARα), Acyl-CoA Synthetase Long-Chain Family Member 1 (ACSL1) and Retinoid X Receptor α (RXRα).

Figure 3. Regulation of skeletal and cardiac muscle development and function by lncRNAs

(A) Regulation of skeletal myogenesis by lncRNAs. Lnc-MD1 serves as a sponge for microRNAs that target myogenic regulators MEF2C and MAML1. MUNC regulates myogenesis through MyoD-dependent and independent mechanisms. The H19 lncRNA transcript induces two microRNAs that antagonize the inhibitory effects of Smad on myocyte differentiation. Yam-1 is a target gene of the transcription factor YY1 that negatively regulates skeletal myogenesis. (B) Regulation of cardiac myocyte development and function by lncRNAs. Bvht promotes cardiovascular lineage commitment and is required for activation of a core cardiovascular gene network through the regulation of MesP1. Mhrt is cardiac-specific lncRNA transcripts that responds to pathologic stress in the heart and plays a protective role in cardiomyopathy. APF promotes autophagic cell death and myocardial infarction through its regulation of ATG7. LncRNAs were shown in blue, microRNAs were shown in white, proteins were shown in grey. The abbreviations are as the following: Myocyte-specific enhancer factor 2C (MEF2C), Mastermind-like protein 1 (MAML1), MyoD upstream noncoding (MUNC), Yin Yang 1 (YY1), Brave heart (Bvht), Suppressor of zeste 12 homolog (SUZ12), Mesoderm posterior 1 (MesP1), Myosin heavy-chain-associated RNA transcript (Mhrt), Brahma-related gene 1 (Brg1), Autophagy-promoting factor (APF) and Autophagy Related 7 (ATG7).

Figure 4. Regulation of other metabolically relevant cell types by lncRNAs

(A) HI-LNC25 is a β cell-specific lncRNA that is required for maintaining the expression of GLIS3. The sno-lncRNAs originated from the PWS locus modulate energy balance through their actions in the central nervous system. (B) Regulation of immune response by lncRNAs. LincRNA-Cox2 and PACER are two lncRNAs originated from the Cox2 gene locus that regulate cytokine signaling. E330013P06 is regulated by nutrients in macrophages and promotes inflammatory signaling. NKILA and Lethe are both cytokine-inducible lncRNAs that serve as negative feedback regulator of NF-κB. THRIL mediates the induction of TNFα gene expression in macrophages in response to proinflammatory stimuli. LncRNAs and protein were shown in blue and grey, respectively. The abbreviations are as the following: GLI-similar 3 (GLIS3), Prader-Willi syndrome (PWS), Toll-like receptor (TLR), Heterogeneous nuclear ribonucleoprotein (hnRNP), p50-associated COX-2 extragenic RNA (PACER), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NF-κB interacting lncRNA (NKILA), LncRNA pseudogene (Lethe), Tumor necrosis factor α (TNFα) and TNFα and hnRNP L related immunoregulatory LincRNA (THRIL).