title: The noncoding RNA Mistral activates Hoxa6 and Hoxa7 expression and stem cell differentiation by recruiting MLL1 to chromatin.
abstract: The epigenetic activator Mixed lineage leukemia 1 (MLL1) is paramount for embryonic development and hematopoiesis. Here, we demonstrate that the long, noncoding RNA (lncRNA) Mistral (Mira) activates transcription of the homeotic genes Hoxa6 and Hoxa7 in mouse embryonic stem cells (mESC) by recruiting MLL1 to chromatin. The Mira gene is located in the spacer DNA region (SDR) separating Hoxa6 and Hoxa7, transcriptionally silent in mESCs, and activated by retinoic acid. Mira-mediated recruitment of MLL1 to the Mira gene triggers dynamic changes in chromosome conformation, culminating in activation of Hoxa6 and Hoxa7 transcription. Hoxa6 and Hoxa7 activate the expression of genes involved in germ layer specification during mESC differentiation in a cooperative and redundant fashion. Our results connect the lncRNA Mira with the recruitment of MLL1 to target genes and implicate lncRNAs in epigenetic activation of gene expression during vertebrate cell-fate determination.
authors.affiliation: Department of Biochemistry, University of California, Riverside, Riverside, CA 92521, USA.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bertani
authors.forename: Silvia
authors.initials: S
authors.lastname: Sauer
authors.forename: Eugene
authors.initials: E
authors.lastname: Bolotin
authors.forename: Frank
authors.initials: F
authors.lastname: Sauer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002843:Chromatin / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D022661:RNA, Untranslated / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; C498560:Hoxa6 protein, mouse; C492047:Hoxa7 protein, mouse; D009363:Neoplasm Proteins; D022661:RNA, Untranslated; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse