MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters

Mixed-lineage leukemia (MLL) maintains the expression of cellular memory genes during development, while leukemic MLL fusion proteins aberrantly maintain expression of hematopoietic stem cell program genes such as HOXA9 to cause leukemia. However, the molecular mechanism of gene activation is unclea...

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Main Authors:	Okuda, Hiroshi, Kawaguchi, Marie, Kanai, Akinori, Matsui, Hirotaka, Kawamura, Takeshi, Inaba, Toshiya, Kitabayashi, Issay, Yokoyama, Akihiko
Format:	Online
Language:	English
Published:	Oxford University Press 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985622/

id	pubmed-3985622
recordtype	oai_dc
spelling	pubmed-39856222014-04-18 MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters Okuda, Hiroshi Kawaguchi, Marie Kanai, Akinori Matsui, Hirotaka Kawamura, Takeshi Inaba, Toshiya Kitabayashi, Issay Yokoyama, Akihiko Gene Regulation, Chromatin and Epigenetics Mixed-lineage leukemia (MLL) maintains the expression of cellular memory genes during development, while leukemic MLL fusion proteins aberrantly maintain expression of hematopoietic stem cell program genes such as HOXA9 to cause leukemia. However, the molecular mechanism of gene activation is unclear. Here we show that only two functional modules are necessary and sufficient for target recognition: those that bind to non-methylated CpGs and di-/tri-methylated histone H3 lysine 36 (H3K36me2/3). An artificial protein composed of the two targeting modules and an interaction domain for AF4-family coactivators can functionally substitute for MLL fusion proteins. Because H3K36me2/3 markers are indicative of active transcription, MLL fusion proteins target previously active CpG-rich genes and activate transcription by recruiting coactivators thereto. Our results indicate that such chromatin context-dependent gene activation is the fundamental mechanism by which MLL fusion proteins maintain the expression of the cellular memory/hematopoietic stem cell program genes. Oxford University Press 2014-04 2014-01-23 /pmc/articles/PMC3985622/ /pubmed/24465000 http://dx.doi.org/10.1093/nar/gkt1394 Text en © The Author(s) 2014. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
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	Okuda, Hiroshi Kawaguchi, Marie Kanai, Akinori Matsui, Hirotaka Kawamura, Takeshi Inaba, Toshiya Kitabayashi, Issay Yokoyama, Akihiko
spellingShingle	Okuda, Hiroshi Kawaguchi, Marie Kanai, Akinori Matsui, Hirotaka Kawamura, Takeshi Inaba, Toshiya Kitabayashi, Issay Yokoyama, Akihiko MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters
author_facet	Okuda, Hiroshi Kawaguchi, Marie Kanai, Akinori Matsui, Hirotaka Kawamura, Takeshi Inaba, Toshiya Kitabayashi, Issay Yokoyama, Akihiko
author_sort	Okuda, Hiroshi
title	MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters
title_short	MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters
title_full	MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters
title_fullStr	MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters
title_full_unstemmed	MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters
title_sort	mll fusion proteins link transcriptional coactivators to previously active cpg-rich promoters
description	Mixed-lineage leukemia (MLL) maintains the expression of cellular memory genes during development, while leukemic MLL fusion proteins aberrantly maintain expression of hematopoietic stem cell program genes such as HOXA9 to cause leukemia. However, the molecular mechanism of gene activation is unclear. Here we show that only two functional modules are necessary and sufficient for target recognition: those that bind to non-methylated CpGs and di-/tri-methylated histone H3 lysine 36 (H3K36me2/3). An artificial protein composed of the two targeting modules and an interaction domain for AF4-family coactivators can functionally substitute for MLL fusion proteins. Because H3K36me2/3 markers are indicative of active transcription, MLL fusion proteins target previously active CpG-rich genes and activate transcription by recruiting coactivators thereto. Our results indicate that such chromatin context-dependent gene activation is the fundamental mechanism by which MLL fusion proteins maintain the expression of the cellular memory/hematopoietic stem cell program genes.
publisher	Oxford University Press
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985622/
_version_	1612077694121410560

MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters

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