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The Caenorhabditis elegans Heterochronic Regulator LIN-14 Is a Novel Transcription Factor That Controls the Developmental Timing of Transcription from the Insulin/Insulin-Like Growth Factor Gene ins-33 by Direct DNA Binding

Marta Hristova,^1, Darcy Birse,^2, Yang Hong,^1, and Victor Ambros^1*

Dartmouth Medical School, Department of Genetics, Hanover, New Hampshire 03755,¹ Stockholm University, Department of Biochemistry and Biophysics, SE-106 91 Stockholm, Sweden²

Received 4 July 2005/ Returned for modification 8 August 2005/ Accepted 16 September 2005

A temporal gradient of the novel nuclear protein LIN-14 specifies the timing and sequence of stage-specific developmental events in Caenorhabditis elegans. The profound effects of lin-14 mutations on worm development suggest that LIN-14 directly or indirectly regulates stage-specific gene expression. We show that LIN-14 can associate with chromatin in vivo and has in vitro DNA binding activity. A bacterially expressed C-terminal domain of LIN-14 was used to select DNA sequences that contain a putative consensus binding site from a pool of randomized double-stranded oligonucleotides. To identify candidates for genes directly regulated by lin-14, we employed DNA microarray hybridization to compare the mRNA abundance of C. elegans genes in wild-type animals to that in mutants with reduced or elevated lin-14 activity. Five of the candidate LIN-14 target genes identified by microarrays, including the insulin/insulin-like growth factor family gene ins-33, contain putative LIN-14 consensus sites in their upstream DNA sequences. Genetic analysis indicates that the developmental regulation of ins-33 mRNA involves the stage-specific repression of ins-33 transcription by LIN-14 via sequence-specific DNA binding. These results reinforce the conclusion that lin-14 encodes a novel class of transcription factor.

Present address: Evanston Northwestern Healthcare Department of Medicine 2650 Ridge Ave., Evanston, IL 60201.

Present address: MDS Pharma Services, Biopharmaceuticals, 22011 30th Drive Southeast, Bothell, WA 98021-4444.

Present address: Howard Hughes Medical Institute, University of California San Francisco, 1550 4th Street, Room GD-481, San Francisco, CA 94143-0725.

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