Poly(ADP-ribosyl)ation is involved in the epigenetic control of TET1 gene transcription

// Fabio Ciccarone 1,2 , Elisabetta Valentini 1,2 , Maria Giulia Bacalini 3 , Michele Zampieri 1,2 , Roberta Calabrese 1,2 , Tiziana Guastafierro 1,2 , Germano Mariano 1,2 , Anna Reale 1,2 , Claudio Franceschi 3 and Paola Caiafa 1,2 1 Department of Cellular Biotechnologies and Hematology, “Sapienza” University of Rome, Rome, Italy 2 Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy 3 Department of Experimental Pathology, Alma Mater Studiorum, University of Bologna, Bologna, Italy Correspondence: Fabio Ciccarone, email: // Paola Caiafa, email: // Keywords : poly(ADP-ribosyl)ation, TET1, DNA methylation, 5-hydroxymethylcytosine Received : February 07, 2014 Accepted : April 16, 2014 Published : April 17, 2014 Abstract TET enzymes are the epigenetic factors involved in the formation of the sixth DNA base 5-hydroxymethylcytosine, whose deregulation has been associated with tumorigenesis. In particular, TET1 acts as tumor suppressor preventing cell proliferation and tumor metastasis and it has frequently been found down-regulated in cancer. Thus, considering the importance of a tight control of TET1 expression, the epigenetic mechanisms involved in the transcriptional regulation of TET1 gene are here investigated. The involvement of poly(ADP-ribosyl)ation in the control of DNA and histone methylation on TET1 gene was examined. PARP activity is able to positively regulate TET1 expressionmaintaining a permissive chromatin state characterized by DNA hypomethylation of TET1 CpG island as well as high levels of H3K4 trimethylation. These epigenetic modifications were affected by PAR depletion causing TET1 down-regulation and in turn reduced recruitment of TET1 protein on HOXA9 target gene. In conclusion, this work shows that PARP activity is a transcriptional regulator of TET1 gene through the control of epigenetic events and it suggests that deregulation of these mechanisms could account for TET1 repression in cancer.