title: A hidden Markov model to identify combinatorial epigenetic regulation patterns for estrogen receptor α target genes.
abstract: BACKGROUND
  Many studies have shown that epigenetic changes, such as altered DNA methylation and histone modifications, are linked to estrogen receptor α (ERα)-positive tumors and disease prognoses. Several recent studies have applied high-throughput technologies such as ChIP-seq and MBD-seq to interrogate the altered architectures of ERα regulation in tamoxifen (Tam)-resistant breast cancer cells. However, the details of combinatorial epigenetic regulation of ERα target genes in breast cancers with acquired Tam resistance have not yet been fully examined.
  
  
  RESULTS
  We developed a computational approach to identify and analyze epigenetic patterns associated with Tam resistance in the MCF7-T cell line as opposed to the Tam-sensitive MCF7 cell line, with the goal of understanding the underlying mechanisms of epigenetic regulatory influence on resistance to Tam treatment in breast cancer. In this study, we used ChIP-seq of ERα, RNA polymerase II, three histone modifications and MBD-seq data of DNA methylation in MCF7 and MCF7-T cells to train hidden Markov models (HMMs). We applied the Bayesian information criterion to determine that a 20-state HMM was best, which was reduced to a 14-state HMM with a Bayesian information criterion score of 1.21291 × 10(7). We further identified four classes of biologically meaningful states in this breast cancer cell model system, and a set of ERα combinatorial epigenetic regulated target genes. The correlated gene expression level and gene ontology analyses showed that different gene ontology terms were enriched with Tam-resistant versus sensitive breast cancer cells. Our study illustrates the applicability of HMM-based analysis of genome-wide high-throughput genomic data to study epigenetic influences on E2/ERα regulation in breast cancer.
authors.affiliation: Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Bonneville
authors.forename: Victor X
authors.initials: VX
authors.lastname: Jin
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001499:Bayes Theorem; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods; D006801:Humans; D061986:MCF-7 Cells; D008390:Markov Chains; D017422:Sequence Analysis, DNA; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D013629:Tamoxifen