IDENTIFICATION OF A NEW SUBCLASS OF ALU DNA REPEATS WHICH CAN FUNCTION AS ESTROGEN RECEPTOR-DEPENDENT TRANSCRIPTIONAL ENHANCERS

We have utilized a genetic selection system in yeast to identify novel estrogen-responsive genes within the hu man genome and to define the sequences in the BRCA-1 gene responsible for its estrogen responsivene ss, This approach led to the identification of a new subclass within t he Alu family of DNA repeats which have diverged from known Alu sequen ces and have acquired the ability to function as estrogen receptor-dep endent enhancers, Importantly, these new elements confer receptor-depe ndent estrogen responsiveness to a heterologous promoter when assayed in mammalian cells, This transcriptional activity can be attenuated by the addition of either of three different classes of estrogen recepto r antagonists, indicating that these elements function as classical es trogen receptor-dependent enhancers, Furthermore, this enhancer activi ty is restricted to a specific subset of DNA repeats because consensus Alu elements of four major subfamilies do not respond to the estrogen receptor. Previously, most Alu sequences have been considered to be f unctionally inert, However, this work provides strong evidence that a significant subset can confer estrogen responsiveness upon a promoter within which they are located, Clearly, Alu sequences must now be cons idered as important contributors to the regulation of gene transcripti on in estrogen receptor-containing cells.