title: LncRNA Khps1 Regulates Expression of the Proto-oncogene SPHK1 via Triplex-Mediated Changes in Chromatin Structure.
abstract: Although thousands of long noncoding RNAs (lncRNAs) have been discovered, very little is known about their mode of action. Here we functionally characterize an E2F1-regulated lncRNA named Khps1, which is transcribed in antisense orientation to the proto-oncogene SPHK1. Khps1 activates SPHK1 expression by recruiting the histone acetyltransferase p300/CBP to the SPHK1 promoter, which leads to local changes of the chromatin structure that ensures E2F1 binding and enhances transcription. Mechanistically, this is achieved by direct association of Khps1 with a homopurine stretch upstream of the transcription start site of SPHK1, which forms a DNA-RNA triplex that anchors the lncRNA and associated effector proteins to the gene promoter. The results reveal an lncRNA- and E2F1-driven regulatory loop in which E2F1-dependent induction of antisense RNA leads to changes in chromatin structure, facilitating E2F1-dependent expression of SPHK1 and restriction of E2F1-induced apoptosis.
authors.affiliation: Division of Molecular Biology of the Cell II, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Postepska-Igielska
authors.affiliation: Division of Molecular Biology of the Cell II, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Alena
authors.initials: A
authors.lastname: Giwojna
authors.affiliation: The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 5299, Israel.
authors.forename: Lital
authors.initials: L
authors.lastname: Gasri-Plotnitsky
authors.affiliation: Division of Molecular Biology of the Cell II, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Schmitt
authors.affiliation: Division of Molecular Biology of the Cell II, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Dold
authors.affiliation: The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 5299, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Ginsberg
authors.affiliation: Division of Molecular Biology of the Cell II, German Cancer Research Center, 69120 Heidelberg, Germany. Electronic address: i.grummt@dkfz.de.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Grummt
mesh_terms: D017209:Apoptosis; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D009690:Nucleic Acid Conformation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D062085:RNA, Long Noncoding / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D050687:E2F1 Transcription Factor; D017853:Phosphotransferases (Alcohol Group Acceptor); D000090063:Proto-Oncogene Mas; D062085:RNA, Long Noncoding; D050880:p300-CBP Transcription Factors; D000099157:Sphingosine Kinase; C493753:E2F1 protein, human; C000605705:Khps1 long noncoding RNA, human; C000715470:MAS1 protein, human
keywords: E2F1; Khps1; SPHK1; antisense; chromatin; lncRNA; p300; triplex