Neat1 is a p53-inducible lincRNA essential for transformation suppression

Stephano S. Mello, Carolyn Sinow, Nitin Raj, Pawel K. Mazur, Kathryn Bieging-Rolett, Daniela Kenzelmann Broz, Jamie F.Conklin Imam, Hannes Vogel, Laura D. Wood, Julien Sage, Tetsuro Hirose, Shinichi Nakagawa, John Rinn, Laura D. Attardi

Research output: Contribution to journalArticle

Abstract

The p53 gene is mutated in over half of all cancers, reflecting its critical role as a tumor suppressor. Although p53 is a transcriptional activator that induces myriad target genes, those p53-inducible genes most critical for tumor suppression remain elusive. Here, we leveraged p53 ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) and RNA-seq (RNA sequencing) data sets to identify new p53 target genes, focusing on the noncoding genome. We identify Neat1, a noncoding RNA (ncRNA) constituent of paraspeckles, as a p53 target gene broadly induced by mouse and human p53 in different cell types and by diverse stress signals. Using fibroblasts derived from Neat1−/− mice, we examined the functional role of Neat1 in the p53 pathway. We found that Neat1 is dispensable for cell cycle arrest and apoptosis in response to genotoxic stress. In sharp contrast, Neat1 plays a crucial role in suppressing transformation in response to oncogenic signals. Neat1 deficiency enhances transformation in oncogene-expressing fibroblasts and promotes the development of premalignant pancreatic intraepithelial neopla-sias (PanINs) and cystic lesions in KrasG12D-expressing mice. Neat1 loss provokes global changes in gene expression, suggesting a mechanism by which its deficiency promotes neoplasia. Collectively, these findings identify Neat1 as a p53-regulated large intergenic ncRNA (lincRNA) with a key role in suppressing transformation and cancer initiation, providing fundamental new insight into p53-mediated tumor suppression.

Original languageEnglish (US)
Pages (from-to)1095-1108
Number of pages14
JournalGenes and Development
Volume31
Issue number11
DOIs
StatePublished - 2017

Keywords

  • LincRNA
  • Neat1
  • P53
  • Pancreatic cancer
  • Tumor suppression

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Fingerprint Dive into the research topics of 'Neat1 is a p53-inducible lincRNA essential for transformation suppression'. Together they form a unique fingerprint.

  • Cite this

    Mello, S. S., Sinow, C., Raj, N., Mazur, P. K., Bieging-Rolett, K., Broz, D. K., Imam, J. F. C., Vogel, H., Wood, L. D., Sage, J., Hirose, T., Nakagawa, S., Rinn, J., & Attardi, L. D. (2017). Neat1 is a p53-inducible lincRNA essential for transformation suppression. Genes and Development, 31(11), 1095-1108. https://doi.org/10.1101/gad.284661.116