Control of transcriptional pausing by biased thermal fluctuations on repetitive genomic sequences.
In the process of transcription elongation, RNA polymerase (RNAP) pauses at highly nonrandom positions across genomic DNA, broadly regulating transcription; however, molecular mechanisms responsible for the recognition of such pausing positions remain poorly understood. Here, using a combination of statistical mechanical modeling and high-throughput sequencing and biochemical data, we evaluate the effect of thermal fluctuations on the regulation of RNAP pausing. We demonstrate that diffusive backtracking of RNAP, which is biased by repetitive DNA sequence elements, causes transcriptional pausing. This effect stems from the increased microscopic heterogeneity of an elongation complex, and thus is entropy-dominated. This report shows a linkage between repetitive sequence elements encoded in the genome and regulation of RNAP pausing driven by thermal fluctuations.
Center for Cancer Research, National Cancer Institute, Frederick, MD 21702; lukatsky@bgu.ac.il imashi@ims.u-tokyo.ac.jp.|Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8673, Japan.|Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Masahiko
M
Imashimizu
Department of Chemistry, Ben-Gurion University of the Negev, Be'er Sheva 8410501, Israel.|Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710.
Ariel
A
Afek
Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8673, Japan.|Molecular Chirality Research Center, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
Hiroki
H
Takahashi
Center for Cancer Research, National Cancer Institute, Frederick, MD 21702.
Lucyna
L
Lubkowska
Department of Chemistry, Ben-Gurion University of the Negev, Be'er Sheva 8410501, Israel; lukatsky@bgu.ac.il imashi@ims.u-tokyo.ac.jp.
David B
DB
Lukatsky
D012321:DNA-Directed RNA Polymerases / Q000378:metabolism*; D019277:Entropy; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D012329:RNA, Bacterial / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D017423:Sequence Analysis, RNA; D013696:Temperature; D014158:Transcription, Genetic
D029968:Escherichia coli Proteins; D012329:RNA, Bacterial; D012321:DNA-Directed RNA Polymerases
RNA polymerase; backtracking; nonconsensus protein–DNA binding; repetitive DNA sequence elements; thermal fluctuations