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Genomic context sensitizes regulatory elements to genetic disruption.
Ordoñez, Raquel; Zhang, Weimin; Ellis, Gwen; Zhu, Yinan; Ashe, Hannah J; Ribeiro-Dos-Santos, André M; Brosh, Ran; Huang, Emily; Hogan, Megan S; Boeke, Jef D; Maurano, Matthew T.
Afiliação
  • Ordoñez R; Institute for Systems Genetics, NYU School of Medicine, New York, NY 10016, USA.
  • Zhang W; Institute for Systems Genetics, NYU School of Medicine, New York, NY 10016, USA.
  • Ellis G; Institute for Systems Genetics, NYU School of Medicine, New York, NY 10016, USA.
  • Zhu Y; Institute for Systems Genetics, NYU School of Medicine, New York, NY 10016, USA.
  • Ashe HJ; Institute for Systems Genetics, NYU School of Medicine, New York, NY 10016, USA.
  • Ribeiro-Dos-Santos AM; Institute for Systems Genetics, NYU School of Medicine, New York, NY 10016, USA.
  • Brosh R; Institute for Systems Genetics, NYU School of Medicine, New York, NY 10016, USA.
  • Huang E; Institute for Systems Genetics, NYU School of Medicine, New York, NY 10016, USA.
  • Hogan MS; Institute for Systems Genetics, NYU School of Medicine, New York, NY 10016, USA.
  • Boeke JD; Institute for Systems Genetics, NYU School of Medicine, New York, NY 10016, USA; Department of Biochemistry Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA; Department of Biomedical Engineering, NYU Tandon School of Engineering, Brooklyn, NY 11201, USA.
  • Maurano MT; Institute for Systems Genetics, NYU School of Medicine, New York, NY 10016, USA; Department of Pathology, NYU School of Medicine, New York, NY 10016, USA. Electronic address: maurano@nyu.edu.
Mol Cell ; 84(10): 1842-1854.e7, 2024 May 16.
Article em En | MEDLINE | ID: mdl-38759624
ABSTRACT
Genomic context critically modulates regulatory function but is difficult to manipulate systematically. The murine insulin-like growth factor 2 (Igf2)/H19 locus is a paradigmatic model of enhancer selectivity, whereby CTCF occupancy at an imprinting control region directs downstream enhancers to activate either H19 or Igf2. We used synthetic regulatory genomics to repeatedly replace the native locus with 157-kb payloads, and we systematically dissected its architecture. Enhancer deletion and ectopic delivery revealed previously uncharacterized long-range regulatory dependencies at the native locus. Exchanging the H19 enhancer cluster with the Sox2 locus control region (LCR) showed that the H19 enhancers relied on their native surroundings while the Sox2 LCR functioned autonomously. Analysis of regulatory DNA actuation across cell types revealed that these enhancer clusters typify broader classes of context sensitivity genome wide. These results show that unexpected dependencies influence even well-studied loci, and our approach permits large-scale manipulation of complete loci to investigate the relationship between regulatory architecture and function.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fator de Crescimento Insulin-Like II / Elementos Facilitadores Genéticos / Fatores de Transcrição SOXB1 / RNA Longo não Codificante / Fator de Ligação a CCCTC Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fator de Crescimento Insulin-Like II / Elementos Facilitadores Genéticos / Fatores de Transcrição SOXB1 / RNA Longo não Codificante / Fator de Ligação a CCCTC Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article