PMID- 28282036
OWN - NLM
STAT- MEDLINE
DCOM- 20180215
LR  - 20181113
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 24
IP  - 5
DP  - 2017 May
TI  - Heterarchy of transcription factors driving basal and luminal cell phenotypes in 
      human urothelium.
PG  - 809-818
LID - 10.1038/cdd.2017.10 [doi]
AB  - Cell differentiation is affected by complex networks of transcription factors 
      that co-ordinate re-organisation of the chromatin landscape. The hierarchies of 
      these relationships can be difficult to dissect. During in vitro differentiation 
      of normal human uro-epithelial cells, formaldehyde-assisted isolation of 
      regulatory elements (FAIRE-seq) and RNA-seq was used to identify alterations in 
      chromatin accessibility and gene expression changes following activation of the 
      nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) as a 
      differentiation-initiating event. Regions of chromatin identified by FAIRE-seq, 
      as having altered accessibility during differentiation, were found to be enriched 
      with sequence-specific binding motifs for transcription factors predicted to be 
      involved in driving basal and differentiated urothelial cell phenotypes, 
      including forkhead box A1 (FOXA1), P63, GRHL2, CTCF and GATA-binding protein 3 
      (GATA3). In addition, co-occurrence of GATA3 motifs was observed within subsets 
      of differentiation-specific peaks containing P63 or FOXA1. Changes in abundance 
      of GRHL2, GATA3 and P63 were observed in immunoblots of chromatin-enriched 
      extracts. Transient siRNA knockdown of P63 revealed that P63 favoured a 
      basal-like phenotype by inhibiting differentiation and promoting expression of 
      basal marker genes. GATA3 siRNA prevented differentiation-associated 
      downregulation of P63 protein and transcript, and demonstrated positive feedback 
      of GATA3 on PPARG transcript, but showed no effect on FOXA1 transcript or protein 
      expression. This approach indicates that as a transcriptionally regulated 
      programme, urothelial differentiation operates as a heterarchy, wherein GATA3 is 
      able to co-operate with FOXA1 to drive expression of luminal marker genes, but 
      that P63 has potential to transrepress expression of the same genes.
FAU - Fishwick, Carl
AU  - Fishwick C
AD  - Jack Birch Unit for Molecular Carcinogenesis, Department of Biology, University 
      of York, York YO10 5DD, UK.
FAU - Higgins, Janet
AU  - Higgins J
AUID- ORCID: 0000-0002-7560-2212
AD  - Earlham Institute, Norwich Research Park, Norwich NR4 7UZ, UK.
FAU - Percival-Alwyn, Lawrence
AU  - Percival-Alwyn L
AUID- ORCID: 0000-0001-7725-9203
AD  - Earlham Institute, Norwich Research Park, Norwich NR4 7UZ, UK.
FAU - Hustler, Arianna
AU  - Hustler A
AD  - Jack Birch Unit for Molecular Carcinogenesis, Department of Biology, University 
      of York, York YO10 5DD, UK.
FAU - Pearson, Joanna
AU  - Pearson J
AD  - Jack Birch Unit for Molecular Carcinogenesis, Department of Biology, University 
      of York, York YO10 5DD, UK.
FAU - Bastkowski, Sarah
AU  - Bastkowski S
AD  - Earlham Institute, Norwich Research Park, Norwich NR4 7UZ, UK.
FAU - Moxon, Simon
AU  - Moxon S
AD  - Earlham Institute, Norwich Research Park, Norwich NR4 7UZ, UK.
FAU - Swarbreck, David
AU  - Swarbreck D
AD  - Earlham Institute, Norwich Research Park, Norwich NR4 7UZ, UK.
FAU - Greenman, Chris D
AU  - Greenman CD
AD  - School of Computing Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
FAU - Southgate, Jennifer
AU  - Southgate J
AUID- ORCID: 0000-0002-0135-480X
AD  - Jack Birch Unit for Molecular Carcinogenesis, Department of Biology, University 
      of York, York YO10 5DD, UK.
LA  - eng
GR  - BB/J010375/1/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170310
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - 0 (CCCTC-Binding Factor)
RN  - 0 (CTCF protein, human)
RN  - 0 (Chromatin)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (FOXA1 protein, human)
RN  - 0 (GATA3 Transcription Factor)
RN  - 0 (GATA3 protein, human)
RN  - 0 (GRHL2 protein, human)
RN  - 0 (Hepatocyte Nuclear Factor 3-alpha)
RN  - 0 (PPAR gamma)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (TP63 protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 1HG84L3525 (Formaldehyde)
SB  - IM
MH  - CCCTC-Binding Factor/genetics/metabolism
MH  - Cell Differentiation/*genetics
MH  - Cell Line
MH  - Chromatin/chemistry/metabolism
MH  - DNA-Binding Proteins/genetics/metabolism
MH  - Epithelial Cells/*cytology/*metabolism
MH  - Formaldehyde/chemistry
MH  - GATA3 Transcription Factor/antagonists & inhibitors/*genetics/metabolism
MH  - Gene Expression Regulation
MH  - Hepatocyte Nuclear Factor 3-alpha/antagonists & inhibitors/*genetics/metabolism
MH  - Humans
MH  - PPAR gamma/genetics/metabolism
MH  - Phenotype
MH  - RNA, Messenger/genetics/metabolism
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Regulatory Elements, Transcriptional
MH  - Sequence Analysis, RNA
MH  - Signal Transduction
MH  - Transcription Factors/antagonists & inhibitors/*genetics/metabolism
MH  - Tumor Suppressor Proteins/antagonists & inhibitors/*genetics/metabolism
MH  - Urothelium/cytology/metabolism
PMC - PMC5423105
COIS- The authors declare no conflict of interest.
EDAT- 2017/03/11 06:00
MHDA- 2018/02/16 06:00
PMCR- 2017/05/01
CRDT- 2017/03/11 06:00
PHST- 2016/07/24 00:00 [received]
PHST- 2017/01/10 00:00 [revised]
PHST- 2017/01/11 00:00 [accepted]
PHST- 2017/03/11 06:00 [pubmed]
PHST- 2018/02/16 06:00 [medline]
PHST- 2017/03/11 06:00 [entrez]
PHST- 2017/05/01 00:00 [pmc-release]
AID - cdd201710 [pii]
AID - 10.1038/cdd.2017.10 [doi]
PST - ppublish
SO  - Cell Death Differ. 2017 May;24(5):809-818. doi: 10.1038/cdd.2017.10. Epub 2017 
      Mar 10.