title: HSA21 Single-Minded 2 (Sim2) Binding Sites Co-Localize with Super-Enhancers and Pioneer Transcription Factors in Pluripotent Mouse ES Cells.
abstract: The HSA21 encoded Single-minded 2 (SIM2) transcription factor has key neurological functions and is a good candidate to be involved in the cognitive impairment of Down syndrome. We aimed to explore the functional capacity of SIM2 by mapping its DNA binding sites in mouse embryonic stem cells. ChIP-sequencing revealed 1229 high-confidence SIM2-binding sites. Analysis of the SIM2 target genes confirmed the importance of SIM2 in developmental and neuronal processes and indicated that SIM2 may be a master transcription regulator. Indeed, SIM2 DNA binding sites share sequence specificity and overlapping domains of occupancy with master transcription factors such as SOX2, OCT4 (Pou5f1), NANOG or KLF4. The association between SIM2 and these pioneer factors is supported by co-immunoprecipitation of SIM2 with SOX2, OCT4, NANOG or KLF4. Furthermore, the binding of SIM2 marks a particular sub-category of enhancers known as super-enhancers. These regions are characterized by typical DNA modifications and Mediator co-occupancy (MED1 and MED12). Altogether, we provide evidence that SIM2 binds a specific set of enhancer elements thus explaining how SIM2 can regulate its gene network in neuronal features.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Letourneau
authors.affiliation: Department of Biophysics, Biochemistry and General Pathology, Seconda Università di Napoli, Napoli, Italy.
authors.forename: Gilda
authors.initials: G
authors.lastname: Cobellis
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Japan.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Fort
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Federico
authors.initials: F
authors.lastname: Santoni
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Garieri
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Falconnet
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Pascale
authors.initials: P
authors.lastname: Ribaux
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Vannier
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Japan.
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Christelle
authors.initials: C
authors.lastname: Borel
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; University Hospitals of Geneva, Geneva, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, Geneva, Switzerland.
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001665:Binding Sites; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D000090062:Kruppel-Like Factor 4; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors; C000715468:Klf4 protein, mouse; C486578:Sim2 protein, mouse