Integrative Transcriptome Analyses of Metabolic Responses in Mice Define Pivotal LncRNA Metabolic Regulators.

To systemically identify long noncoding RNAs (lncRNAs) regulating energy metabolism, we performed transcriptome analyses to simultaneously profile mRNAs and lncRNAs in key metabolic organs in mice under pathophysiologically representative metabolic conditions. Of 4,759 regulated lncRNAs, function-oriented filters yield 359 tissue-specifically regulated and metabolically sensitive lncRNAs that are predicted by lncRNA-mRNA correlation analyses to function in diverse aspects of energy metabolism. Specific regulations of liver metabolically sensitive lncRNAs (lncLMS) by nutrients, metabolic hormones, and key transcription factors were further defined in primary hepatocytes. Combining genome-wide screens, bioinformatics function predictions, and cell-based analyses, we developed an integrative roadmap to identify lncRNA metabolic regulators. An lncLMS was experimentally confirmed in mice to suppress lipogenesis by forming a negative feedback loop in the SREBP1c pathway. Taken together, this study supports that a class of lncRNAs function as important metabolic regulators and establishes a framework for systemically investigating the role of lncRNAs in physiological homeostasis.

A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice.

Long non-coding RNAs (lncRNAs) constitute a significant portion of mammalian genome, yet the physiological importance of lncRNAs is largely unknown. Here, we identify a liver-enriched lncRNA in mouse that we term liver-specific triglyceride regulator (lncLSTR). Mice with a liver-specific depletion of lncLSTR exhibit a marked reduction in plasma triglyceride levels. We show that lncLSTR depletion enhances apoC2 expression, leading to robust lipoprotein lipase activation and increased plasma triglyceride clearance. We further demonstrate that the regulation of apoC2 expression occurs through an FXR-mediated pathway. LncLSTR forms a molecular complex with TDP-43 to regulate expression of Cyp8b1, a key enzyme in the bile acid synthesis pathway, and engenders an in vivo bile pool that induces apoC2 expression through FXR. Finally, we demonstrate that lncLSTR depletion can reduce triglyceride levels in a hyperlipidemia mouse model. Taken together, these data support a model in which lncLSTR regulates a TDP-43/FXR/apoC2-dependent pathway to maintain systemic lipid homeostasis.

Distinct polyadenylation landscapes of diverse human tissues revealed by a modified PA-seq strategy.

BACKGROUND: Polyadenylation is a key regulatory step in eukaryotic gene expression and one of the major contributors of transcriptome diversity. Aberrant polyadenylation often associates with expression defects and leads to human diseases. RESULTS: To better understand global polyadenylation regulation, we have developed a polyadenylation sequencing (PA-seq) approach. By profiling polyadenylation events in 13 human tissues, we found that alternative cleavage and polyadenylation (APA) is prevalent in both protein-coding and noncoding genes. In addition, APA usage, similar to gene expression profiling, exhibits tissue-specific signatures and is sufficient for determining tissue origin. A 3' untranslated region shortening index (USI) was further developed for genes with tandem APA sites. Strikingly, the results showed that different tissues exhibit distinct patterns of shortening and/or lengthening of 3' untranslated regions, suggesting the intimate involvement of APA in establishing tissue or cell identity. CONCLUSIONS: This study provides a comprehensive resource to uncover regulated polyadenylation events in human tissues and to characterize the underlying regulatory mechanism.

Human down syndrome cell adhesion molecules (DSCAMs) are functionally conserved with Drosophila Dscam[TM1] isoforms in controlling neurodevelopment.

Drosophila Down syndrome cell adhesion molecule (Dscam) potentially produces more than 150,000 cell adhesion molecules that share two alternative transmembrane/juxtamembrane (TM) domains, which dictate the dendrite versus axon subcellular distribution and function of different Dscam isoforms. Vertebrate genomes contain two closely related genes, DSCAM and DSCAM-Like1 (DSCAML1), which do not have extensive alternative splicing. We investigated the functional conservation between invertebrate Dscams and vertebrate DSCAMs by cross-species rescue assays and found that human DSCAM and DSCAML1 partially, but substantially, rescued the larval lethality of Drosophila Dscam mutants. Interestingly, both human DSCAM and DSCAML1 were targeted to the dendrites in Drosophila neurons, had synergistic rescue effects with Drosophila Dscam[TM2], and preferentially rescued the dendrite defects of Drosophila Dscam mutant neurons. Therefore, human DSCAM and DSCAML1 are functionally conserved with Drosophila Dscam[TM1] isoforms.