Article abstract
Nature Structural & Molecular Biology 15, 146 - 154 (2008)
Published online: 13 January 2008 | doi:10.1038/nsmb.1372
The functional response of upstream DNA to dynamic supercoiling in vivo
Fedor Kouzine1, Suzanne Sanford1, Zichrini Elisha-Feil1 & David Levens1
Abstract
Because RNA polymerase is a powerful motor, transmission of transcription-generated forces might directly alter DNA structure, chromatin or gene activity in mammalian cells. Here we show that transcription-generated supercoils streaming dynamically from active promoters have considerable consequences for DNA structure and function in cells. Using a tamoxifen-activatable Cre recombinase to excise a test segment of chromatin positioned between divergently transcribed metallothionein-IIa promoters, we found the degree of dynamic supercoiling to increase as transcription intensified, and it was very sensitive to the specific arrangement of promoters and cis elements. Using psoralen as an in vivo probe confirmed that, during transcription, sufficient supercoiling is produced to enable transitions to conformations other than B-DNA in elements such as the human MYC far upstream element (FUSE), which in turn recruit structure-sensitive regulatory proteins, such as FUSE Binding Protein (FBP) and FBP-Interacting Repressor (FIR). These results indicate that mechanical stresses, constrained by architectural features of DNA and chromatin, may broadly contribute to gene regulation.
- Laboratory of Pathology, National Cancer Institute, 10 Center Drive, Building 10, Room 2N106, Bethesda, Maryland 20892-1500, USA.
Correspondence to: David Levens1 e-mail: levens@helix.nih.gov
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