PMID- 30566157
OWN - NLM
STAT- MEDLINE
DCOM- 20200504
LR  - 20200505
IS  - 1756-591X (Electronic)
IS  - 1756-5901 (Linking)
VI  - 11
IP  - 2
DP  - 2019 Feb 20
TI  - Copper affects the binding of HIF-1alpha to the critical motifs of its target genes.
PG  - 429-438
LID - 10.1039/c8mt00280k [doi]
AB  - Copper (Cu) regulates hypoxia-inducible factor-1 (HIF-1) transcription activity 
      by affecting the selectivity of HIF-1alpha binding to the promoters of affected 
      genes. In hypoxia, Cu is required for HIF-1alpha binding to the promoter of 
      BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), but the metal 
      does not affect the binding of HIF-1alpha to the promoter of insulin-like growth 
      factor 2 (IGF2). Here, we made an effort to provide a comprehensive understanding 
      of Cu regulation of the selectivity of HIF-1alpha binding across the genome. We used 
      tetraethylenepentamine (TEPA), a Cu selective chelator, to reduce Cu content in 
      the cells. We conducted chromatin immunoprecipitation combined with massively 
      parallel DNA sequencing (ChIP-seq) to globally map the binding sites of HIF-1alpha, 
      RNA polymerase II (Pol II), and the acetylation at the 27th lysine residue of the 
      histone H3 protein (H3K27ac). We also performed RNA-sequencing (RNA-seq) in 
      EA.hy926 cells under hypoxia (1% O2) with or without Cu depression to determine 
      the profile of mRNA expression. Our analyses identified 3197 HIF-1alpha binding sites 
      under hypoxia. Cu depression by TEPA reduced the number of binding sites to 1820 
      from the original 3197, but induced 274 new binding sites. We analysed these 
      binding sites in the promoter and putative enhancer regions, coupled with their 
      mRNA expression profiles, and found 281 Cu-dependent and 10 Cu-independent HIF-1alpha 
      target genes. We found that the core bases "GGAA" and "TTCC" constituted the 
      critical motifs for the binding sites of Cu-dependent genes. This study thus 
      revealed that Cu, by affecting the binding of HIF-1alpha to the critical motifs in 
      the promoter and putative enhancer regions of HIF-1 regulated genes, leads to the 
      selectivity of HIF-1 regulated expression of Cu-dependent genes.
FAU - Wu, Zhijuan
AU  - Wu Z
AD  - Regenerative Medicine Research Center, Sichuan University West China Hospital, 
      Chengdu, Sichuan 610041, China. ykang7@uthsc.edu.
FAU - Zhang, Wenjing
AU  - Zhang W
FAU - Kang, Y James
AU  - Kang YJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Metallomics
JT  - Metallomics : integrated biometal science
JID - 101478346
RN  - 0 (Ethylenediamines)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 789U1901C5 (Copper)
RN  - EC 2.7.7.- (RNA Polymerase II)
RN  - YZD1C9KQ28 (tetraethylenepentamine)
SB  - IM
MH  - Binding Sites/genetics
MH  - Blotting, Western
MH  - Cell Line
MH  - Chromatin Immunoprecipitation
MH  - Copper
MH  - Ethylenediamines/metabolism
MH  - Gene Expression Regulation/genetics
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Promoter Regions, Genetic/genetics
MH  - RNA Polymerase II/metabolism
EDAT- 2018/12/20 06:00
MHDA- 2020/05/06 06:00
CRDT- 2018/12/20 06:00
PHST- 2018/12/20 06:00 [pubmed]
PHST- 2020/05/06 06:00 [medline]
PHST- 2018/12/20 06:00 [entrez]
AID - 10.1039/c8mt00280k [doi]
PST - ppublish
SO  - Metallomics. 2019 Feb 20;11(2):429-438. doi: 10.1039/c8mt00280k.