Attenuation of Forkhead signaling by the retinal determination factor DACH1

Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6864-9. doi: 10.1073/pnas.1002746107. Epub 2010 Mar 29.

Abstract

The Drosophila Dachshund (Dac) gene, cloned as a dominant inhibitor of the hyperactive growth factor mutant ellipse, encodes a key component of the retinal determination gene network that governs cell fate. Herein, cyclic amplification and selection of targets identified a DACH1 DNA-binding sequence that resembles the FOX (Forkhead box-containing protein) binding site. Genome-wide in silico promoter analysis of DACH1 binding sites identified gene clusters populating cellular pathways associated with the cell cycle and growth factor signaling. ChIP coupled with high-throughput sequencing mapped DACH1 binding sites to corresponding gene clusters predicted in silico and identified as weight matrix resembling the cyclic amplification and selection of targets-defined sequence. DACH1 antagonized FOXM1 target gene expression, promoter occupancy in the context of local chromatin, and contact-independent growth. Attenuation of FOX function by the cell fate determination pathway has broad implications given the diverse role of FOX proteins in cellular biology and tumorigenesis.

Publication types

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

MeSH terms

  • Binding Sites
  • Cell Lineage
  • Chromatin / chemistry
  • Computational Biology / methods
  • DNA / chemistry
  • Eye Proteins / metabolism*
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation
  • Genome
  • HeLa Cells
  • Humans
  • Promoter Regions, Genetic
  • Protein Binding
  • Retina / metabolism*
  • Signal Transduction
  • Transcription Factors / metabolism*

Substances

  • Chromatin
  • DACH1 protein, human
  • Eye Proteins
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Transcription Factors
  • DNA