title: Global Transcriptome Analysis Reveals That Poly(ADP-Ribose) Polymerase 1 Regulates Gene Expression through EZH2.
abstract: Posttranslational modifications, such as poly(ADP-ribosyl)ation (PARylation), regulate chromatin-modifying enzymes, ultimately affecting gene expression. This study explores the role of poly(ADP-ribose) polymerase (PARP) on global gene expression in a lymphoblastoid B cell line. We found that inhibition of PARP catalytic activity with olaparib resulted in global gene deregulation, affecting approximately 11% of the genes expressed. Gene ontology analysis revealed that PARP could exert these effects through transcription factors and chromatin-remodeling enzymes, including the polycomb repressive complex 2 (PRC2) member EZH2. EZH2 mediates the trimethylation of histone H3 at lysine 27 (H3K27me3), a modification associated with chromatin compaction and gene silencing. Both pharmacological inhibition of PARP and knockdown of PARP1 induced the expression of EZH2, which resulted in increased global H3K27me3. Chromatin immunoprecipitation confirmed that PARP1 inhibition led to H3K27me3 deposition at EZH2 target genes, which resulted in gene silencing. Moreover, increased EZH2 expression is attributed to the loss of the occupancy of the transcription repressor E2F4 at the EZH2 promoter following PARP inhibition. Together, these data show that PARP plays an important role in global gene regulation and identifies for the first time a direct role of PARP1 in regulating the expression and function of EZH2.
authors.affiliation: Fels Institute for Cancer and Molecular Biology, Temple University, Philadelphia, Pennsylvania, USA.
authors.forename: Kayla A
authors.initials: KA
authors.lastname: Martin
authors.affiliation: Fels Institute for Cancer and Molecular Biology, Temple University, Philadelphia, Pennsylvania, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cesaroni
authors.affiliation: Section of Rheumatology, Temple University, Philadelphia, Pennsylvania, USA Department of Microbiology and Immunology, Temple University, Philadelphia, Pennsylvania, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Denny
authors.affiliation: Fels Institute for Cancer and Molecular Biology, Temple University, Philadelphia, Pennsylvania, USA.
authors.forename: Lena N
authors.initials: LN
authors.lastname: Lupey
authors.affiliation: Fels Institute for Cancer and Molecular Biology, Temple University, Philadelphia, Pennsylvania, USA Department of Microbiology and Immunology, Temple University, Philadelphia, Pennsylvania, USA tempera@temple.edu.
authors.forename: Italo
authors.initials: I
authors.lastname: Tempera
mesh_terms: D002460:Cell Line; D000071221:Enhancer of Zeste Homolog 2 Protein; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic
chemical_list: D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases