KORNBLIHTT Alberto Rodolfo
Progesterone receptor induces bcl-x expression through intragenic binding sites favoring RNA Polymerase II elongation
BERTUCCI, P.; NACHT, A.; ALLÓ, M.; ROCHA-VIEGAS, L.; BALLARÉ, C.; SORONELLAS, D.; CASTELLANO, G.; ZAURIN, R.; KORNBLIHTT, A. R.; BEATO, M.; VICENT, G.; PECCI, A.
NUCLEIC ACIDS RESEARCH
OXFORD UNIV PRESS
Año: 2014 vol. 41 p. 6072 - 6072
Hormone receptors regulate transcription through complex mechanisms mediated by their recruitment along with co-regulators to binding sites at variable distance from the promoters of hormone-target genes. A large proportion of these sites are located in intronic regions. To determine the role of these sites on transcription regulation, we examined the response of the bcl-x gene to the progestin R5020 in T47D breast cancer cells, as several intragenic Progesterone Receptor binding sites (PRbs) were identified in this gene . We show here that in response to hormone PR is recruited to these sites together with two histone acetyltransferases CBP and GCN5, leading to increased acetylation of histone H3 and H4 and binding of the BAF57 subunit of the SWI/SNF complex. The combination of these events during bcl-x induction, promoted the formation of a relaxed chromatin at the distal intragenic PRbs, as demonstrated by enhanced DNase I hypersensitivity. Activated PR also interacted directly with the elongation factor pTEFb and mediated its recruitment to the intragenic PRbs. As a result, there was a re-distribution of RNA polymerase II (Pol II) toward the 3´end of the gene and a decrease in the ratio between proximal and distal transcription. These results suggest that PR can modulate the transcription levels of target genes by a direct effect on transcription elongation, occurring at two levels: first, by relaxing the chromatin substrate and second, by recruiting elongation factors, both required for proper Pol II passage.