Mixed Integer Linear Programming based machine learning approach identifies regulators of telomerase in yeast

Nucleic Acids Res. 2016 Jun 2;44(10):e93. doi: 10.1093/nar/gkw111. Epub 2016 Feb 22.

Abstract

Understanding telomere length maintenance mechanisms is central in cancer biology as their dysregulation is one of the hallmarks for immortalization of cancer cells. Important for this well-balanced control is the transcriptional regulation of the telomerase genes. We integrated Mixed Integer Linear Programming models into a comparative machine learning based approach to identify regulatory interactions that best explain the discrepancy of telomerase transcript levels in yeast mutants with deleted regulators showing aberrant telomere length, when compared to mutants with normal telomere length. We uncover novel regulators of telomerase expression, several of which affect histone levels or modifications. In particular, our results point to the transcription factors Sum1, Hst1 and Srb2 as being important for the regulation of EST1 transcription, and we validated the effect of Sum1 experimentally. We compiled our machine learning method leading to a user friendly package for R which can straightforwardly be applied to similar problems integrating gene regulator binding information and expression profiles of samples of e.g. different phenotypes, diseases or treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Regulation, Fungal*
  • Gene Regulatory Networks
  • Histones / genetics
  • Histones / metabolism
  • Machine Learning*
  • Mediator Complex / genetics
  • Mutation
  • Nuclear Proteins / genetics
  • Programming, Linear
  • Repressor Proteins / genetics
  • Reproducibility of Results
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics*
  • Sirtuin 2 / genetics
  • Software
  • Telomerase / genetics*

Substances

  • Histones
  • Mediator Complex
  • Nuclear Proteins
  • Repressor Proteins
  • SRB2 protein, S cerevisiae
  • SUM1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • EST1 protein, S cerevisiae
  • Telomerase
  • HST1 protein, S cerevisiae
  • Sirtuin 2