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      Interrogation of nonconserved human adipose lincRNAs identifies a regulatory role of linc-ADAL in adipocyte metabolism

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          Abstract

          Long intergenic noncoding RNAs (lincRNAs) have emerged as important modulators of cellular functions. Most lincRNAs are not conserved among mammals, raising the fundamental question of whether nonconserved adipose-expressed lincRNAs are functional. To address this, we performed deep RNA sequencing of gluteal subcutaneous adipose tissue from 25 healthy humans. We identified 1001 putative lincRNAs expressed in all samples through de novo reconstruction of noncoding transcriptomes and integration with existing lincRNA annotations. One hundred twenty lincRNAs had adipose-enriched expression, and 54 of these exhibited peroxisome proliferator–activated receptor γ (PPARγ) or CCAAT/enhancer binding protein α (C/EBPα) binding at their loci. Most of these adipose-enriched lincRNAs (~85%) were not conserved in mice, yet on average, they showed degrees of expression and binding of PPARγ and C/EBPα similar to those displayed by conserved lincRNAs. Most adipose lincRNAs differentially expressed ( n = 53) in patients after bariatric surgery were nonconserved. The most abundant adipose-enriched lincRNA in our subcutaneous adipose data set, linc-ADAL, was nonconserved, up-regulated in adipose depots of obese individuals, and markedly induced during in vitro human adipocyte differentiation. We demonstrated that linc-ADAL interacts with heterogeneous nuclear ribonucleoprotein U (hnRNPU) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) at distinct subcellular locations to regulate adipocyte differentiation and lipogenesis.

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          Long noncoding RNA as modular scaffold of histone modification complexes.

          Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.
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            The evolutionary landscape of alternative splicing in vertebrate species.

            How species with similar repertoires of protein-coding genes differ so markedly at the phenotypic level is poorly understood. By comparing organ transcriptomes from vertebrate species spanning ~350 million years of evolution, we observed significant differences in alternative splicing complexity between vertebrate lineages, with the highest complexity in primates. Within 6 million years, the splicing profiles of physiologically equivalent organs diverged such that they are more strongly related to the identity of a species than they are to organ type. Most vertebrate species-specific splicing patterns are cis-directed. However, a subset of pronounced splicing changes are predicted to remodel protein interactions involving trans-acting regulators. These events likely further contributed to the diversification of splicing and other transcriptomic changes that underlie phenotypic differences among vertebrate species.
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              Streaming fragment assignment for real-time analysis of sequencing experiments

              We present eXpress, a software package for highly efficient probabilistic assignment of ambiguously mapping sequenced fragments. eXpress uses a streaming algorithm with linear run time and constant memory use. It can determine abundances of sequenced molecules in real time, and can be applied to ChIP-seq, metagenomics and other large-scale sequencing data. We demonstrate its use on RNA-seq data, showing greater efficiency than other quantification methods.
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                Author and article information

                Journal
                101505086
                36963
                Sci Transl Med
                Sci Transl Med
                Science translational medicine
                1946-6234
                1946-6242
                28 June 2019
                20 June 2018
                10 July 2019
                : 10
                : 446
                : eaar5987
                Affiliations
                [1 ]Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
                [2 ]Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
                [3 ]Division of Cardiovascular Medicine, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
                [4 ]Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
                [5 ]Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
                [6 ]Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
                [7 ]Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, China.
                [8 ]Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
                [9 ]The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
                [10 ]Divisions of Human Genetics and Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45267, USA.
                [11 ]Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
                [12 ]Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
                [13 ]Irving Institute for Clinical and Translational Research, Columbia University, New York, NY 10032, USA.
                Author notes

                Author contributions: X.Z. and M.P.R. conceived the study, conducted experiments, and wrote the paper with assistance and input from J.L., R.E.S., J.B.H., and P.S. J.F.F. participated in design and execution of the clinical study and collected human adipose samples. B.D.G. and S.G. prepared RNA-seq libraries for adipose samples and helped with quality control and data analysis. C.X. and M.H. performed analysis on RNA-seq and ChIP-seq data with input from M.L. A.W., Y.H., and B.A.G. performed mass spectrometry analysis for adipose coding transcript screening and RNA pulldown experiments. H.J. performed liquid chromatography mass spectrometry for de novo lipogenesis measurement. W. Liu, C.H., and W. Li assisted with data collection for in vitro adipocyte studies.

                [* ]Corresponding author. mpr2144@ 123456cumc.columbia.edu
                Article
                PMC6620026 PMC6620026 6620026 nihpa1035425
                10.1126/scitranslmed.aar5987
                6620026
                29925637
                dd727579-0b33-4a23-80fa-540393110d5a
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