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Am J Hum Genet. 2019 Oct 3;105(4):677-688. doi: 10.1016/j.ajhg.2019.08.003. Epub 2019 Sep 5.

cis Elements that Mediate RNA Polymerase II Pausing Regulate Human Gene Expression.

Author information

1
Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
2
Howard Hughes Medical Institute, Chevy Chase, MD, USA.
3
Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
4
National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD, USA.
5
Howard Hughes Medical Institute, Chevy Chase, MD, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA; Department of Pediatrics, Division of Neurology, University of Michigan, Ann Arbor, MI, USA. Electronic address: vgcheung@med.umich.edu.

Abstract

Aberrant gene expression underlies many human diseases. RNA polymerase II (Pol II) pausing is a key regulatory step in transcription. Here, we mapped the locations of RNA Pol II in normal human cells and found that RNA Pol II pauses in a consistent manner across individuals and cell types. At more than 1,000 genes including MYO1E and SESN2, RNA Pol II pauses at precise nucleotide locations. Characterization of these sites shows that RNA Pol II pauses at GC-rich regions that are marked by a sequence motif. Sixty-five percent of the pause sites are cytosines. By differential allelic gene expression analysis, we showed in our samples and a population dataset from the Genotype-Tissue Expression (GTEx) consortium that genes with more paused polymerase have lower expression levels. Furthermore, mutagenesis of the pause sites led to a significant increase in promoter activities. Thus, our data uncover that RNA Pol II pauses precisely at sites with distinct sequence features that in turn regulate gene expression.

KEYWORDS:

RNA polymerase; RNA polymerase pausing; gene expression; transcription

PMID:
31495490
PMCID:
PMC6817524
[Available on 2020-04-03]
DOI:
10.1016/j.ajhg.2019.08.003
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