Nup98 recruits the Wdr82–Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells
- Tobias M. Franks1,
- Asako McCloskey1,
- Maxim Nikolaievich Shokhirev2,
- Chris Benner1,3,
- Annie Rathore1 and
- Martin W. Hetzer1
- 1Laboratory of Molecular and Cellular Biology, Salk Institute for Biological Studies, La Jolla, California 92037, USA;
- 2The Razavi Newman Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, California 92037, USA;
- 3Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA
- Corresponding author: hetzer{at}salk.edu
Abstract
Recent studies have shown that a subset of nucleoporins (Nups) can detach from the nuclear pore complex and move into the nuclear interior to regulate transcription. One such dynamic Nup, called Nup98, has been implicated in gene activation in healthy cells and has been shown to drive leukemogenesis when mutated in patients with acute myeloid leukemia (AML). Here we show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82–Set1A/COMPASS (complex of proteins associated with Set1) complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark. Depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and subsequently ablates H3K4me3 at adjacent promoters. Furthermore, expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at abnormal regions and up-regulation of associated genes. Our findings establish a function of Nup98 in hematopoietic gene activation and provide mechanistic insight into which Nup98 leukemic fusion proteins promote AML.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.306753.117.
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Freely available online through the Genes & Development Open Access option.
- Received September 8, 2017.
- Accepted November 21, 2017.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
