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Cellular zinc status alters chromatin accessibility and binding of transcription factor p53 to genomic sites.


ABSTRACT: Zinc (Zn2+) is an essential metal required by approximately 2500 proteins. Nearly half of these proteins act on DNA, including > 850 human transcription factors, polymerases, DNA damage response factors, and proteins involved in chromatin architecture. How these proteins acquire their essential Zn2+ cofactor and whether they are sensitive to changes in the labile Zn2+ pool in cells remain open questions. Here, we examine how changes in the labile Zn2+ pool affect chromatin accessibility and transcription factor binding to DNA. We observed both increases and decreases in accessibility in different chromatin regions via ATAC-seq upon treating MCF10A cells with elevated Zn2+ or the Zn2+-specific chelator tris(2-pyridylmethyl)amine (TPA). Transcription factor enrichment analysis was used to correlate changes in chromatin accessibility with transcription factor motifs, revealing 477 transcription factor motifs that were differentially enriched upon Zn2+ perturbation. 186 of these transcription factor motifs were enriched in Zn2+ and depleted in TPA, and the majority correspond to Zn2+ finger transcription factors. We selected TP53 as a candidate to examine how changes in motif enrichment correlate with changes in transcription factor occupancy by ChIP-qPCR. Using publicly available ChIP-seq and nascent transcription datasets, we narrowed the 50,000+ ATAC-seq peaks to 2164 TP53 targets and subsequently selected 6 high-probability TP53 binding sites for testing. ChIP-qPCR revealed that for 5 of the 6 targets, TP53 binding correlates with the local accessibility determined by ATAC-seq. These results demonstrate that changes in labile zinc directly alter chromatin accessibility and transcription factor binding to DNA.

SUBMITTER: Damon LJ 

PROVIDER: S-EPMC10690171 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Cellular zinc status alters chromatin accessibility and binding of transcription factor p53 to genomic sites.

Damon Leah J LJ   Ocampo Daniel D   Sanford Lynn L   Jones Taylor T   Allen Mary A MA   Dowell Robin D RD   Palmer Amy E AE  

bioRxiv : the preprint server for biology 20231121


Zinc (Zn<sup>2+</sup>) is an essential metal required by approximately 2500 proteins. Nearly half of these proteins act on DNA, including > 850 human transcription factors, polymerases, DNA damage response factors, and proteins involved in chromatin architecture. How these proteins acquire their essential Zn<sup>2+</sup> cofactor and whether they are sensitive to changes in the labile Zn<sup>2+</sup> pool in cells remain open questions. Here, we examine how changes in the labile Zn<sup>2+</sup>  ...[more]

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