Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes

The nucleoporin Nup98 is frequently rearranged to form leukemogenic Nup98-fusion proteins with various partners. However, their function remains largely elusive. Here, we show that Nup98-HoxA9, a fusion between Nup98 and the homeobox transcription factor HoxA9, forms nuclear aggregates that frequent...

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Main Authors:	Oka, Masahiro, Mura, Sonoko, Yamada, Kohji, Sangel, Percival, Hirata, Saki, Maehara, Kazumitsu, Kawakami, Koichi, Tachibana, Taro, Ohkawa, Yasuyuki, Kimura, Hiroshi, Yoneda, Yoshihiro
Format:	Online
Language:	English
Published:	eLife Sciences Publications, Ltd 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718815/

id	pubmed-4718815
recordtype	oai_dc
spelling	pubmed-47188152016-01-21 Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes Oka, Masahiro Mura, Sonoko Yamada, Kohji Sangel, Percival Hirata, Saki Maehara, Kazumitsu Kawakami, Koichi Tachibana, Taro Ohkawa, Yasuyuki Kimura, Hiroshi Yoneda, Yoshihiro Cell Biology The nucleoporin Nup98 is frequently rearranged to form leukemogenic Nup98-fusion proteins with various partners. However, their function remains largely elusive. Here, we show that Nup98-HoxA9, a fusion between Nup98 and the homeobox transcription factor HoxA9, forms nuclear aggregates that frequently associate with facultative heterochromatin. We demonstrate that stable expression of Nup98-HoxA9 in mouse embryonic stem cells selectively induces the expression of Hox cluster genes. Genome-wide binding site analysis revealed that Nup98-HoxA9 is preferentially targeted and accumulated at Hox cluster regions where the export factor Crm1 is originally prebound. In addition, leptomycin B, an inhibitor of Crm1, disassembled nuclear Nup98-HoxA9 dots, resulting in the loss of chromatin binding of Nup98-HoxA9 and Nup98-HoxA9-mediated activation of Hox genes. Collectively, our results indicate that highly selective targeting of Nup98-fusion proteins to Hox cluster regions via prebound Crm1 induces the formation of higher order chromatin structures that causes aberrant Hox gene regulation. eLife Sciences Publications, Ltd 2016-01-07 /pmc/articles/PMC4718815/ /pubmed/26740045 http://dx.doi.org/10.7554/eLife.09540 Text en © 2015, Oka et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Oka, Masahiro Mura, Sonoko Yamada, Kohji Sangel, Percival Hirata, Saki Maehara, Kazumitsu Kawakami, Koichi Tachibana, Taro Ohkawa, Yasuyuki Kimura, Hiroshi Yoneda, Yoshihiro
spellingShingle	Oka, Masahiro Mura, Sonoko Yamada, Kohji Sangel, Percival Hirata, Saki Maehara, Kazumitsu Kawakami, Koichi Tachibana, Taro Ohkawa, Yasuyuki Kimura, Hiroshi Yoneda, Yoshihiro Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes
author_facet	Oka, Masahiro Mura, Sonoko Yamada, Kohji Sangel, Percival Hirata, Saki Maehara, Kazumitsu Kawakami, Koichi Tachibana, Taro Ohkawa, Yasuyuki Kimura, Hiroshi Yoneda, Yoshihiro
author_sort	Oka, Masahiro
title	Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes
title_short	Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes
title_full	Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes
title_fullStr	Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes
title_full_unstemmed	Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes
title_sort	chromatin-prebound crm1 recruits nup98-hoxa9 fusion to induce aberrant expression of hox cluster genes
description	The nucleoporin Nup98 is frequently rearranged to form leukemogenic Nup98-fusion proteins with various partners. However, their function remains largely elusive. Here, we show that Nup98-HoxA9, a fusion between Nup98 and the homeobox transcription factor HoxA9, forms nuclear aggregates that frequently associate with facultative heterochromatin. We demonstrate that stable expression of Nup98-HoxA9 in mouse embryonic stem cells selectively induces the expression of Hox cluster genes. Genome-wide binding site analysis revealed that Nup98-HoxA9 is preferentially targeted and accumulated at Hox cluster regions where the export factor Crm1 is originally prebound. In addition, leptomycin B, an inhibitor of Crm1, disassembled nuclear Nup98-HoxA9 dots, resulting in the loss of chromatin binding of Nup98-HoxA9 and Nup98-HoxA9-mediated activation of Hox genes. Collectively, our results indicate that highly selective targeting of Nup98-fusion proteins to Hox cluster regions via prebound Crm1 induces the formation of higher order chromatin structures that causes aberrant Hox gene regulation.
publisher	eLife Sciences Publications, Ltd
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718815/
_version_	1613525861485510656

Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes

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