Attenuation of Forkhead signaling by the retinal determination factor DACH1.
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.
Zhou
Jie
J
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Wang
Chenguang
C
Wang
Zhibin
Z
Dampier
Will
W
Wu
Kongming
K
Casimiro
Mathew C
MC
Chepelev
Iouri
I
Popov
Vladimir M
VM
Quong
Andrew
A
Tozeren
Aydin
A
Zhao
Keji
K
Lisanti
Michael P
MP
Pestell
Richard G
RG
D001665:Binding Sites; D019070:Cell Lineage; D002843:Chromatin / Q000737:chemistry; D019295:Computational Biology / Q000379:methods; D004247:DNA / Q000737:chemistry; D005136:Eye Proteins / Q000378:metabolism*; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D016678:Genome; D006367:HeLa Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012160:Retina / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D002843:Chromatin; C486747:DACH1 protein, human; D005136:Eye Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; D004247:DNA