Bypassing the Requirements for Epigenetic Modifications in Gene Transcription by Increasing Enhancer Strength

Abstract

Our current concept postulates that histone acetylation is required for the recruitment of bromodomain-containing transcription complexes, such as the chromatin-remodeling machine SWI/SNF and the basal transcription factor TFIID. We generated simple NF-κB-dependent enhancers of increasing transcriptional strengths and found that the histone acetylation requirements for activation of transcription depended on the strengths of these enhancers. All enhancers function by recruiting SWI/SNF and TFIID to induce nucleosome sliding, a prerequisite for transcriptional activation. However, histone acetylation, although it occurs, is dispensable for TFIID and SWI/SNF recruitment by the strong enhancers, indicating that strong activators can overcome the chromatin barrier by directly recruiting the necessary transcriptional complexes. Weak enhancers depend on histone acetylation for recruitment, and this requirement is independent of a histone acetylation code. Thus, the need for nucleosome modifications is imposed on genes and translated according to the quality and strengths of the activators.

ACKNOWLEDGMENTS

We thank Mark Ptashne, Stavros Lomvardas, George Panayotou, and Ethan Ford for critical reading of the manuscript and helpful suggestions.

This work was supported by the Greek Secretariat for Research and Technology (PENED 01ED225), the Leukemia and Lymphoma Society of America, the March of Dimes, the Human Frontiers Science Program, Philip Morris USA Inc., and Philip Morris International.