The key role of differential broad H3K4me3 and H3K4ac domains in breast cancer

Camila López, Mohammad T. Barnon, Tasnim H. Beacon, Gino Nardocci, James R. Davie*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Epigenetic processes are radically altered in cancer cells. The altered epigenetic events may include histone post-translational modifications (PTMs), DNA modifications, and/or alterations in the levels and modifications of chromatin modifying enzymes and chromatin remodelers. With changes in gene programming are changes in the genomic distribution of histone PTMs. Genes that are poised or transcriptionally active have histone H3 trimethylated lysine 4 (H3K4me3) located at the transcription start site and at the 5′ end of the gene. However, a small population of genes that are involved in cell identity or cancer cell properties have a broad H3K4me3 domain that may stretch for several kilobases through the coding region of the gene. Each cancer cell type appears to mark a select set of cancer-related genes in this manner. In this study, we determined which genes were differentially marked with the broad H3K4me3 domain in normal-like (MCF10A), luminal-type breast cancer (MCF7), and triple-negative breast cancer (MDA-MB-231) cells. We also determined whether histone H3 acetylated lysine 4 (H3K4ac), also a mark of active promoters, had a broad domain configuration. We applied two peak callers (MACS2, PeakRanger) to analyze H3K4me3 and H3K4ac chromatin immunoprecipitation sequencing (ChIP-Seq) data. We identified genes with a broad H3K4me3 and/or H3K4ac domain specific to each cell line and show that the genes have critical roles in the breast cancer subtypes. Furthermore, we show that H3K4ac marks enhancers. The identified genes with the broad H3K4me3/H3K4ac domain have been targeted in clinical and pre-clinical studies including therapeutic treatments of breast cancer.

Original languageEnglish
Article number146463
Pages (from-to)146463
JournalGene
Volume826
DOIs
StatePublished - 5 Jun 2022

Bibliographical note

Funding Information:
Research support by grant from Natural Sciences and Engineering Research Council of Canada (RGPIN-2017-05927) and CancerCare Manitoba (761020451) to JRD and ANID/CONICYT - FONDECYT de Iniciación (11190998) and ANID- Basal funding for Scientific and Technological Center of Excellence, IMPACT (FB210024), to GN. We acknowledge that the CancerCare Manitoba Research Institute and the University of Manitoba campuses are located on original lands of Anishinaabeg, Cree, Oji-Cree, Dakota and Dene peoples, and on the homeland of the Métis Nation.

Funding Information:
Research support by grant from Natural Sciences and Engineering Research Council of Canada (RGPIN-2017-05927) and CancerCare Manitoba (761020451) to JRD and ANID/CONICYT - FONDECYT de Iniciaci?n (11190998) and ANID- Basal funding for Scientific and Technological Center of Excellence, IMPACT (FB210024), to GN. We acknowledge that the CancerCare Manitoba Research Institute and the University of Manitoba campuses are located on original lands of Anishinaabeg, Cree, Oji-Cree, Dakota and Dene peoples, and on the homeland of the M?tis Nation. Conceptualization: J.R.D.; The first draft was prepared by C.L.; Analyses of ChIP Seq and RNA Seq data using MACS2 was done by T.H.B. G.N. and J.R.D.; PeakRanger analyses was done by M.T.B.; Interpretation of the data was done by all authors; Writing of the manuscript was done by all authors. All authors have read and agreed to the published version of the manuscript. James R Davie https://orcid.org/ 0000-0002-0420-6888.

Publisher Copyright:
© 2022 Elsevier B.V.

Keywords

  • Active histone marks
  • Breast cancer
  • Broad H3K4ac domains
  • Broad H3K4me3 domains
  • Enhancer

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