A nonnatural transcriptional coactivator

A nonnatural transcriptional coactivator

^*Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138; and ^†Department of Chemistry, Yale University, 225 Prospect Street, P.O. Box 208107, New Haven, CT 06520

Edited by Stuart L. Schreiber, Harvard University, Cambridge, MA, and approved September 17, 1997 (received for review August 15, 1997)

Abstract

In eukaryotes, sequence-specific DNA-binding proteins activate gene expression by recruiting the transcriptional apparatus and chromatin remodeling proteins to the promoter through protein-protein contacts. In many instances, the connection between DNA-binding proteins and the transcriptional apparatus is established through the intermediacy of adapter proteins known as coactivators. Here we describe synthetic molecules with low molecular weight that act as transcriptional coactivators. We demonstrate that a completely nonnatural activation domain in one such molecule is capable of stimulating transcription in vitro and in vivo. The present strategy provides a means of gaining external control over gene activation through intervention using small molecules.

Footnotes

↵ ‡ To whom reprint requests should be addressed. e-mail: verdine{at}chemistry.harvard.edu.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviation: SEAP, secreted alkaline phosphatase.
A commentary on this article begins on page 13388.