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

Oncotarget. 2014 Nov 15;5(21):10356-67. doi: 10.18632/oncotarget.1905.

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 expression maintaining 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Breast Neoplasms / genetics*
  • DNA Methylation / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Histones / genetics
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Jurkat Cells
  • MCF-7 Cells
  • Mixed Function Oxygenases
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Transcription, Genetic / genetics

Substances

  • DNA-Binding Proteins
  • Histones
  • Homeodomain Proteins
  • Proto-Oncogene Proteins
  • homeobox protein HOXA9
  • Adenosine Diphosphate
  • Mixed Function Oxygenases
  • TET1 protein, human
  • Poly(ADP-ribose) Polymerases