PMID- 21283829
OWN - NLM
STAT- MEDLINE
DCOM- 20110802
LR  - 20220310
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 1
DP  - 2011 Jan 19
TI  - Genomewide analyses define different modes of transcriptional regulation by 
      peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta).
PG  - e16344
LID - 10.1371/journal.pone.0016344 [doi]
LID - e16344
AB  - Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with 
      essential functions in lipid, glucose and energy homeostasis, cell 
      differentiation, inflammation and metabolic disorders, and represent important 
      drug targets. PPARs heterodimerize with retinoid X receptors (RXRs) and can form 
      transcriptional activator or repressor complexes at specific DNA elements 
      (PPREs). It is believed that the decision between repression and activation is 
      generally governed by a ligand-mediated switch. We have performed genomewide 
      analyses of agonist-treated and PPARbeta/delta-depleted human myofibroblasts to test 
      this hypothesis and to identify global principles of PPARbeta/delta-mediated gene 
      regulation. Chromatin immunoprecipitation sequencing (ChIP-Seq) of PPARbeta/delta, 
      H3K4me3 and RNA polymerase II enrichment sites combined with transcriptional 
      profiling enabled the definition of 112 bona fide PPARbeta/delta target genes showing 
      either of three distinct types of transcriptional response: (I) 
      ligand-independent repression by PPARbeta/delta; (II) ligand-induced activation and/or 
      derepression by PPARbeta/delta; and (III) ligand-independent activation by PPARbeta/delta. 
      These data identify PPRE-mediated repression as a major mechanism of 
      transcriptional regulation by PPARbeta/delta, but, unexpectedly, also show that only a 
      subset of repressed genes are activated by a ligand-mediated switch. Our results 
      also suggest that the type of transcriptional response by a given target gene is 
      connected to the structure of its associated PPRE(s) and the biological function 
      of its encoded protein. These observations have important implications for 
      understanding the regulatory PPAR network and PPARbeta/delta ligand-based drugs.
FAU - Adhikary, Till
AU  - Adhikary T
AD  - Institute of Molecular Biology and Tumor Research, Philipps University, Marburg, 
      Germany.
FAU - Kaddatz, Kerstin
AU  - Kaddatz K
FAU - Finkernagel, Florian
AU  - Finkernagel F
FAU - Schonbauer, Anne
AU  - Schonbauer A
FAU - Meissner, Wolfgang
AU  - Meissner W
FAU - Scharfe, Maren
AU  - Scharfe M
FAU - Jarek, Michael
AU  - Jarek M
FAU - Blocker, Helmut
AU  - Blocker H
FAU - Muller-Brusselbach, Sabine
AU  - Muller-Brusselbach S
FAU - Muller, Rolf
AU  - Muller R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110119
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (PPAR delta)
RN  - 0 (PPAR-beta)
RN  - 0 (Peroxisome Proliferator-Activated Receptors)
SB  - IM
MH  - Cell Line
MH  - *Gene Expression Regulation
MH  - Gene Regulatory Networks
MH  - Genome, Human/*genetics
MH  - Genome-Wide Association Study
MH  - Humans
MH  - PPAR delta/genetics
MH  - PPAR-beta/genetics
MH  - Peroxisome Proliferator-Activated Receptors/*genetics
MH  - Response Elements
MH  - *Transcription, Genetic
PMC - PMC3023804
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/02/02 06:00
MHDA- 2011/08/04 06:00
PMCR- 2011/01/19
CRDT- 2011/02/02 06:00
PHST- 2010/10/08 00:00 [received]
PHST- 2010/12/11 00:00 [accepted]
PHST- 2011/02/02 06:00 [entrez]
PHST- 2011/02/02 06:00 [pubmed]
PHST- 2011/08/04 06:00 [medline]
PHST- 2011/01/19 00:00 [pmc-release]
AID - PONE-D-10-03204 [pii]
AID - 10.1371/journal.pone.0016344 [doi]
PST - epublish
SO  - PLoS One. 2011 Jan 19;6(1):e16344. doi: 10.1371/journal.pone.0016344.