Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany; Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany; Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
Helene Kretzmer
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
Christian Much
Department of Biochemistry, University of Colorado Boulder and BioFrontiers Institute, Boulder, United States
Max Planck Institute for Molecular Genetics, Microscopy Core Facility, Berlin, Germany
Alina Rose
Helmholtz Institute for Metabolic, Obesity and Vascular Research, Leipzig, Germany
Hua-Jun Wu
Department of Data Science, Dana-Farber Cancer Institute, Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, United States; Center for Precision Medicine Multi-Omics Research, School of Basic Medical Sciences, Peking University Health Science Center and Peking University Cancer Hospital and Institute, Beijing, China
Center for Precision Medicine Multi-Omics Research, School of Basic Medical Sciences, Peking University Health Science Center and Peking University Cancer Hospital and Institute, Beijing, China; Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, United States
Denes Hnisz
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
Franziska Michor
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States; Broad Institute of MIT and Harvard, Cambridge, United States; Department of Data Science, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, United States; The Ludwig Center at Harvard, Boston, MA 02215, USA, and Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, United States
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany; Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States; Broad Institute of MIT and Harvard, Cambridge, United States
Long non-coding RNAs (lncRNAs) have emerged as fundamental regulators in various biological processes, including embryonic development and cellular differentiation. Despite much progress over the past decade, the genome-wide annotation of lncRNAs remains incomplete and many known non-coding loci are still poorly characterized. Here, we report the discovery of a previously unannotated lncRNA that is transcribed 230 kb upstream of the SOX17 gene and located within the same topologically associating domain. We termed it T-REX17 (Transcript Regulating Endoderm and activated by soX17) and show that it is induced following SOX17 activation but its expression is more tightly restricted to early definitive endoderm. Loss of T-REX17 affects crucial functions independent of SOX17 and leads to an aberrant endodermal transcriptome, signaling pathway deregulation and epithelial to mesenchymal transition defects. Consequently, cells lacking the lncRNA cannot further differentiate into more mature endodermal cell types. Taken together, our study identified and characterized T-REX17 as a transiently expressed and essential non-coding regulator in early human endoderm differentiation.
