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Interactions of chromatin context, binding site sequence content, and sequence evolution in stress-induced p53 occupancy and transactivation.

Publication ,  Journal Article
Su, D; Wang, X; Campbell, MR; Song, L; Safi, A; Crawford, GE; Bell, DA
Published in: PLoS Genet
January 2015

Cellular stresses activate the tumor suppressor p53 protein leading to selective binding to DNA response elements (REs) and gene transactivation from a large pool of potential p53 REs (p53REs). To elucidate how p53RE sequences and local chromatin context interact to affect p53 binding and gene transactivation, we mapped genome-wide binding localizations of p53 and H3K4me3 in untreated and doxorubicin (DXR)-treated human lymphoblastoid cells. We examined the relationships among p53 occupancy, gene expression, H3K4me3, chromatin accessibility (DNase 1 hypersensitivity, DHS), ENCODE chromatin states, p53RE sequence, and evolutionary conservation. We observed that the inducible expression of p53-regulated genes was associated with the steady-state chromatin status of the cell. Most highly inducible p53-regulated genes were suppressed at baseline and marked by repressive histone modifications or displayed CTCF binding. Comparison of p53RE sequences residing in different chromatin contexts demonstrated that weaker p53REs resided in open promoters, while stronger p53REs were located within enhancers and repressed chromatin. p53 occupancy was strongly correlated with similarity of the target DNA sequences to the p53RE consensus, but surprisingly, inversely correlated with pre-existing nucleosome accessibility (DHS) and evolutionary conservation at the p53RE. Occupancy by p53 of REs that overlapped transposable element (TE) repeats was significantly higher (p<10-7) and correlated with stronger p53RE sequences (p<10-110) relative to nonTE-associated p53REs, particularly for MLT1H, LTR10B, and Mer61 TEs. However, binding at these elements was generally not associated with transactivation of adjacent genes. Occupied p53REs located in L2-like TEs were unique in displaying highly negative PhyloP scores (predicted fast-evolving) and being associated with altered H3K4me3 and DHS levels. These results underscore the systematic interaction between chromatin status and p53RE context in the induced transactivation response. This p53 regulated response appears to have been tuned via evolutionary processes that may have led to repression and/or utilization of p53REs originating from primate-specific transposon elements.

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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

January 2015

Volume

11

Issue

1

Start / End Page

e1004885

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Transcriptional Activation
  • Response Elements
  • Protein Binding
  • Promoter Regions, Genetic
  • Nucleosomes
  • Humans
  • Histone-Lysine N-Methyltransferase
  • Gene Expression Regulation
  • Doxorubicin
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Su, D., Wang, X., Campbell, M. R., Song, L., Safi, A., Crawford, G. E., & Bell, D. A. (2015). Interactions of chromatin context, binding site sequence content, and sequence evolution in stress-induced p53 occupancy and transactivation. PLoS Genet, 11(1), e1004885. https://doi.org/10.1371/journal.pgen.1004885
Su, Dan, Xuting Wang, Michelle R. Campbell, Lingyun Song, Alexias Safi, Gregory E. Crawford, and Douglas A. Bell. “Interactions of chromatin context, binding site sequence content, and sequence evolution in stress-induced p53 occupancy and transactivation.PLoS Genet 11, no. 1 (January 2015): e1004885. https://doi.org/10.1371/journal.pgen.1004885.
Su D, Wang X, Campbell MR, Song L, Safi A, Crawford GE, et al. Interactions of chromatin context, binding site sequence content, and sequence evolution in stress-induced p53 occupancy and transactivation. PLoS Genet. 2015 Jan;11(1):e1004885.
Su, Dan, et al. “Interactions of chromatin context, binding site sequence content, and sequence evolution in stress-induced p53 occupancy and transactivation.PLoS Genet, vol. 11, no. 1, Jan. 2015, p. e1004885. Pubmed, doi:10.1371/journal.pgen.1004885.
Su D, Wang X, Campbell MR, Song L, Safi A, Crawford GE, Bell DA. Interactions of chromatin context, binding site sequence content, and sequence evolution in stress-induced p53 occupancy and transactivation. PLoS Genet. 2015 Jan;11(1):e1004885.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

January 2015

Volume

11

Issue

1

Start / End Page

e1004885

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Transcriptional Activation
  • Response Elements
  • Protein Binding
  • Promoter Regions, Genetic
  • Nucleosomes
  • Humans
  • Histone-Lysine N-Methyltransferase
  • Gene Expression Regulation
  • Doxorubicin