TY - JOUR
T1 - A p53-bound enhancer region controls a long intergenic noncoding RNA required for p53 stress response
AU - Melo, C. A.
AU - Léveillé, N.
AU - Rooijers, K.
AU - Wijchers, P. J.
AU - Geeven, G.
AU - Tal, A.
AU - Melo, Sónia A.
AU - De Laat, W.
AU - Agami, R.
N1 - Publisher Copyright: © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2016/8/18
Y1 - 2016/8/18
N2 - Genome-wide chromatin studies identified the tumor suppressor p53 as both a promoter and an enhancer-binding transcription factor. As an enhancer factor, p53 can induce local production of enhancer RNAs, as well as transcriptional activation of distal neighboring genes. Beyond the regulation of protein-coding genes, p53 has the capacity to regulate long intergenic noncoding RNA molecules (lincRNAs); however, their importance to the p53 tumor suppressive function remains poorly characterized. Here, we identified and characterized a novel p53-bound intronic enhancer that controls the expression of its host, the lincRNA00475 (linc-475). We demonstrate the requirement of linc-475 for the proper induction of a p53-dependent cell cycle inhibitory response. We further confirm the functional importance of linc-475 in the maintenance of CDKN1A/p21 levels, a cell cycle inhibitor and a major p53 target gene, following p53 activation. Interestingly, loss of linc-475 reduced the binding of both p53 and RNA polymerase II (RNAPII) to the promoter of p21, attenuating its transcription rate following p53 activation. Altogether, our data suggest a direct role of p53-bound enhancer domains in the activation of lincRNAs required for an efficient p53 transcriptional response.
AB - Genome-wide chromatin studies identified the tumor suppressor p53 as both a promoter and an enhancer-binding transcription factor. As an enhancer factor, p53 can induce local production of enhancer RNAs, as well as transcriptional activation of distal neighboring genes. Beyond the regulation of protein-coding genes, p53 has the capacity to regulate long intergenic noncoding RNA molecules (lincRNAs); however, their importance to the p53 tumor suppressive function remains poorly characterized. Here, we identified and characterized a novel p53-bound intronic enhancer that controls the expression of its host, the lincRNA00475 (linc-475). We demonstrate the requirement of linc-475 for the proper induction of a p53-dependent cell cycle inhibitory response. We further confirm the functional importance of linc-475 in the maintenance of CDKN1A/p21 levels, a cell cycle inhibitor and a major p53 target gene, following p53 activation. Interestingly, loss of linc-475 reduced the binding of both p53 and RNA polymerase II (RNAPII) to the promoter of p21, attenuating its transcription rate following p53 activation. Altogether, our data suggest a direct role of p53-bound enhancer domains in the activation of lincRNAs required for an efficient p53 transcriptional response.
UR - http://www.scopus.com/inward/record.url?scp=84954480861&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/onc.2015.502
DO - https://doi.org/10.1038/onc.2015.502
M3 - Article
C2 - 26776159
SN - 0950-9232
VL - 35
SP - 4399
EP - 4406
JO - Oncogene
JF - Oncogene
IS - 33
ER -