Histone H3 lysine 4 acetylation and methylation dynamics define breast cancer subtypes

Messier, Terri L.; Gordon, Jonathan A. R.; Boyd, Joseph R.; Tye, Coralee E.; Browne, Gillian; Stein, Janet L.; Lian, Jane B.

doi:10.18632/oncotarget.6922

Cited by 96 publications

(78 citation statements)

References 51 publications

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“…In line with the WA-specific decrease of chromatin accessibility observed at a DNAse hypersensitive site at the IL6 gene locus [38], the EpiExplorer web tool further revealed significant enrichment of WA induced hypermethylation at DNase hypersensitive sites, promoters and enhancers (Figure 9A) [42]. In addition, upon comparing WA hypermethylated genes to the oncofetal bivalent breast cancer signature of H3K4me3 and H3K27me3 marks, we observed a predominant overlap with H3K4me3 marks (Figure 9B) [54, 55]. Of particular interest, ChIP-seq experiments revealed strong genome-wide gain of H3K4ac and H3K4me3 at gene promoters associated with breast cancer-related phenotypic traits, such as estrogen response and epithelial-to-mesenchymal transition pathways [54, 55].…”

Section: Resultssupporting

confidence: 68%

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Epigenetic silencing of triple negative breast cancer hallmarks by Withaferin A

et al. 2017

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Triple negative breast cancer (TNBC) is characterized by poor prognosis and a DNA hypomethylation profile. Withaferin A (WA) is a plant derived steroidal lactone which holds promise as a therapeutic agent for treatment of breast cancer (BC). We determined genome-wide DNA methylation changes in weakly-metastatic and aggressive, metastatic BC cell lines, following 72h treatment to a sub-cytotoxic concentration of WA. In contrast to the DNA demethylating agent 5-aza-2’-deoxycytidine (DAC), WA treatment of MDA-MB-231 cells rather tackles an epigenetic cancer network through gene-specific DNA hypermethylation of tumor promoting genes including ADAM metallopeptidase domain 8 (ADAM8), urokinase-type plasminogen activator (PLAU), tumor necrosis factor (ligand) superfamily, member 12 (TNFSF12), and genes related to detoxification (glutathione S-transferase mu 1, GSTM1), or mitochondrial metabolism (malic enzyme 3, ME3). Gene expression and pathway enrichment analysis further reveals epigenetic suppression of multiple cancer hallmarks associated with cell cycle regulation, cell death, cancer cell metabolism, cell motility and metastasis. Remarkably, DNA hypermethylation of corresponding CpG sites in PLAU, ADAM8, TNSF12, GSTM1 and ME3 genes correlates with receptor tyrosine-protein kinase erbB-2 amplification (HER2)/estrogen receptor (ESR)/progesterone receptor (PR) status in primary BC tumors. Moreover, upon comparing differentially methylated WA responsive target genes with DNA methylation changes in different clinical subtypes of breast cancer patients in the cancer genome atlas (TCGA), we found that WA silences HER2/PR/ESR-dependent gene expression programs to suppress aggressive TNBC characteristics in favor of luminal BC hallmarks, with an improved therapeutic sensitivity. In this respect, WA may represent a novel and attractive phyto-pharmaceutical for TNBC treatment.

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Section: Resultssupporting

confidence: 68%

“…( B ) Bar charts representing the percentage overlap between WA-induced differentially methylated positions (DMPs) and H3K4me3, H3K27me3 histone marks in MDA-MB-231 cells [54, 55]. Overlap was performed for all the 1722 WA-induced DMPs, including hypermethylated DMPs (hyper-DMPs) and hypomethylated DMPs (hypo-DMPs).…”

Section: Resultsmentioning

confidence: 99%

Epigenetic silencing of triple negative breast cancer hallmarks by Withaferin A

et al. 2017

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“…We targeted 10 loci ( Supplementary Table 1) in four cell lines: three breast cell lines (MCF-10A, MCF-7, and MDA-MB-231) and the wellcharacterized GM12878 lymphoblast cell line. For studying DNA methylation and structural variants, regions of interest were selected based on previous whole-genome nanopore data from our lab 10 as well as existing expression data in these breast cell lines 11 . To evaluate single nucleotide mutations we selected three cancer-associated genes that have annotated mutations in the MDA-MB-231 cell line 12 .…”

Section: Resultsmentioning

confidence: 99%

Targeted Nanopore Sequencing with Cas9 for studies of methylation, structural variants, and mutations

Gilpatrick

Lee

Graham

et al. 2019

Preprint

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Nanopore sequencing technology can rapidly and directly interrogate native DNA molecules. Often we are interested only in interrogating specific areas at high depth, but conventional enrichment methods have thus far proved unsuitable for long reads 1 . Existing strategies are currently limited by high input DNA requirements, low yield, short (<5kb) reads, time-intensive protocols, and/or amplification or cloning (losing base modification information). In this paper, we describe a technique utilizing the ability of Cas9 to introduce cuts at specific locations and ligating nanopore sequencing adaptors directly to those sites, a method we term 'nanopore Cas9 Targeted-Sequencing' (nCATS).We have demonstrated this using an Oxford Nanopore MinION flow cell (Capacity >10Gb+) to generate a median 165X coverage at 10 genomic loci with a median length of 18kb, representing a several hundred-fold improvement over the 2-3X coverage achieved without enrichment. We performed a pilot run on the smaller Flongle flow cell (Capacity ~1Gb), generating a median coverage of 30X at 11 genomic loci with a median length of 18kb. Using panels of guide RNAs, we show that the high coverage data from this method enables us to (1) profile DNA methylation patterns at cancer driver genes, (2) detect structural variations at known hot spots, and (3) survey for the presence of single nucleotide mutations. Together, this provides a low-cost method that can be applied even in low resource settings to directly examine cellular DNA. This technique has extensive clinical applications for assessing medically relevant genes and has the versatility to be a rapid and comprehensive diagnostic tool. We demonstrate applications of this technique by examining the well-characterized GM12878 cell line as well as three breast cell lines (MCF-10A, MCF-7, MDA-MB-231) with varying tumorigenic potential as a model for cancer. ContributionsTG and WT constructed the study. TG performed the experiments. TG, IL, and FS analyzed the data. TG, JG, ER, RB and AH and developed the method. TG and WT wrote the paper

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“…ChIP-seq results were analyzed using established bioinromatics pipeline in our group, and have been published elsewhere [44]. …”

Section: Methodsmentioning

confidence: 99%

An AML1-ETO/miR-29b-1 regulatory circuit modulates phenotypic properties of acute myeloid leukemia cells

et al. 2017

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Acute myeloid leukemia (AML) is characterized by an aggressive clinical course and frequent cytogenetic abnormalities that include specific chromosomal translocations. The 8;21 chromosomal rearrangement disrupts the key hematopoietic RUNX1 transcription factor, and contributes to leukemia through recruitment of co-repressor complexes to RUNX1 target genes, altered subnuclear localization, and deregulation of the myeloid gene regulatory program. However, a role of non-coding microRNAs (miRs) in t(8;21)-mediated leukemogenesis is minimally understood. We present evidence of an interplay between the tumor suppressor miR-29b-1 and the AML1-ETO (also designated RUNX1-RUNX1T1) oncogene that is encoded by the t(8;21). We find that AML1-ETO and corepressor NCoR co-occupy the miR-29a/b-1 locus and downregulate its expression in leukemia cells. Conversely, re-introduction of miR-29b-1 in leukemia cells expressing AML1-ETO causes significant downregulation at the protein level through direct targeting of the 3’ untranslated region of the chimeric transcript. Restoration of miR-29b-1 expression in leukemia cells results in decreased cell growth and increased apoptosis. The AML1-ETO-dependent differentiation block and transcriptional program are partially reversed by miR-29b-1. Our findings establish a novel regulatory circuit between the tumor-suppressive miR-29b-1 and the oncogenic AML1-ETO that controls the leukemic phenotype in t(8;21)-carrying acute myeloid leukemia.

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Histone H3 lysine 4 acetylation and methylation dynamics define breast cancer subtypes

Cited by 96 publications

References 51 publications

Epigenetic silencing of triple negative breast cancer hallmarks by Withaferin A

Epigenetic silencing of triple negative breast cancer hallmarks by Withaferin A

Targeted Nanopore Sequencing with Cas9 for studies of methylation, structural variants, and mutations

An AML1-ETO/miR-29b-1 regulatory circuit modulates phenotypic properties of acute myeloid leukemia cells

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