Genome-wide identification of post-translational modulators of transcription factor activity in human B cells

Nat Biotechnol. 2009 Sep;27(9):829-39. doi: 10.1038/nbt.1563. Epub 2009 Sep 9.

Abstract

The ability of a transcription factor (TF) to regulate its targets is modulated by a variety of genetic and epigenetic mechanisms, resulting in highly context-dependent regulatory networks. However, high-throughput methods for the identification of proteins that affect TF activity are still largely unavailable. Here we introduce an algorithm, modulator inference by network dynamics (MINDy), for the genome-wide identification of post-translational modulators of TF activity within a specific cellular context. When used to dissect the regulation of MYC activity in human B lymphocytes, the approach inferred novel modulators of MYC function, which act by distinct mechanisms, including protein turnover, transcription complex formation and selective enzyme recruitment. MINDy is generally applicable to study the post-translational modulation of mammalian TFs in any cellular context. As such it can be used to dissect context-specific signaling pathways and combinatorial transcriptional regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms*
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / physiology*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • MADS Domain Proteins / genetics
  • MADS Domain Proteins / metabolism
  • MEF2 Transcription Factors
  • Microarray Analysis
  • Models, Genetic*
  • Myogenic Regulatory Factors / genetics
  • Myogenic Regulatory Factors / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational / genetics*
  • Protein Stability
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Reproducibility of Results
  • Signal Transduction
  • Systems Biology / methods
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • BHLHE40 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • MADS Domain Proteins
  • MEF2 Transcription Factors
  • MEF2B protein, human
  • Myogenic Regulatory Factors
  • Proto-Oncogene Proteins c-myc
  • Transcription Factors
  • Protein-Serine-Threonine Kinases
  • STK38 protein, human
  • HDAC1 protein, human
  • Histone Deacetylase 1