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Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes.
Moorthy, Sakthi D; Davidson, Scott; Shchuka, Virlana M; Singh, Gurdeep; Malek-Gilani, Nakisa; Langroudi, Lida; Martchenko, Alexandre; So, Vincent; Macpherson, Neil N; Mitchell, Jennifer A.
Afiliação
  • Moorthy SD; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
  • Davidson S; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
  • Shchuka VM; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
  • Singh G; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
  • Malek-Gilani N; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
  • Langroudi L; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
  • Martchenko A; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
  • So V; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
  • Macpherson NN; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
  • Mitchell JA; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
Genome Res ; 27(2): 246-258, 2017 02.
Article em En | MEDLINE | ID: mdl-27895109
ABSTRACT
Transcriptional enhancers are critical for maintaining cell-type-specific gene expression and driving cell fate changes during development. Highly transcribed genes are often associated with a cluster of individual enhancers such as those found in locus control regions. Recently, these have been termed stretch enhancers or super-enhancers, which have been predicted to regulate critical cell identity genes. We employed a CRISPR/Cas9-mediated deletion approach to study the function of several enhancer clusters (ECs) and isolated enhancers in mouse embryonic stem (ES) cells. Our results reveal that the effect of deleting ECs, also classified as ES cell super-enhancers, is highly variable, resulting in target gene expression reductions ranging from 12% to as much as 92%. Partial deletions of these ECs which removed only one enhancer or a subcluster of enhancers revealed partially redundant control of the regulated gene by multiple enhancers within the larger cluster. Many highly transcribed genes in ES cells are not associated with a super-enhancer; furthermore, super-enhancer predictions ignore 81% of the potentially active regulatory elements predicted by cobinding of five or more pluripotency-associated transcription factors. Deletion of these additional enhancer regions revealed their robust regulatory role in gene transcription. In addition, select super-enhancers and enhancers were identified that regulated clusters of paralogous genes. We conclude that, whereas robust transcriptional output can be achieved by an isolated enhancer, clusters of enhancers acting on a common target gene act in a partially redundant manner to fine tune transcriptional output of their target genes.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transcrição Gênica / Elementos Facilitadores Genéticos / Regulação da Expressão Gênica no Desenvolvimento / Células-Tronco Embrionárias Murinas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transcrição Gênica / Elementos Facilitadores Genéticos / Regulação da Expressão Gênica no Desenvolvimento / Células-Tronco Embrionárias Murinas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article