Dual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression.

Hox genes play important roles in haematopoietic development in mammals. ASH1 is a member of the trithorax group (trxG) that is required for proper expression of Hox genes and is preferentially expressed in haematopoietic stem cells. We have recently reported that ASH1 methylates histone H3 at lysin...

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Autores principales:	Yujiro Tanaka, Koji Kawahashi, Zen-Ichiro Katagiri, Yasuhiro Nakayama, Milind Mahajan, Dimitris Kioussis
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9055b1051b904f7187a6e8be96043fa6
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spelling	oai:doaj.org-article:9055b1051b904f7187a6e8be96043fa62021-11-18T07:33:30ZDual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression.1932-620310.1371/journal.pone.0028171https://doaj.org/article/9055b1051b904f7187a6e8be96043fa62011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22140534/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Hox genes play important roles in haematopoietic development in mammals. ASH1 is a member of the trithorax group (trxG) that is required for proper expression of Hox genes and is preferentially expressed in haematopoietic stem cells. We have recently reported that ASH1 methylates histone H3 at lysine 36 (K36) but its biological function has remained elusive. Here we show that ASH1 regulates Hox gene expression positively and negatively in a leukemic cell line K562 and is required for myelomonocytic differentiation of murine haematopoietic stem cells. ASH1 binds to endogenous Hox loci in K562 cells and its knockdown causes reduced expression of Hox genes. In addition, ASH1 and MLL1 induce more than 100-fold activation of Hox promoters in HeLa cells if expressed simultaneously but not individually. Notably, ASH1 harbouring a point mutation that kills methyltransferase activity is more efficient than wild type ASH1 in Hox gene activation, indicating that K36 methylation is not a prerequisite for Hox gene expression. Moreover, tethering wild type or catalytically inactive methyltransferase domain of ASH1 to a heterologous promoter causes downregulation or upregulation, respectively, of transcription, supporting a hypothesis that K36 methylation imparts repression. Knockdown of ASH1 in K562 cells in vitro causes increased expression of ε-globin gene and reduced expression of myelomonocytic markers GPIIb and GPIIIa, whereas knockdown of ASH1 in murine haematopoietic stem cells in vivo results in decreased number of macrophages and granulocytes, a phenotype similar to that induced by loss of mll1 function. Taken together, our data suggest that ASH1 and MLL1 synergize in activation of Hox genes and thereby regulate development of myelomonocytic lineages from haematopoietic stem cells.Yujiro TanakaKoji KawahashiZen-Ichiro KatagiriYasuhiro NakayamaMilind MahajanDimitris KioussisPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 11, p e28171 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yujiro Tanaka Koji Kawahashi Zen-Ichiro Katagiri Yasuhiro Nakayama Milind Mahajan Dimitris Kioussis Dual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression.
description	Hox genes play important roles in haematopoietic development in mammals. ASH1 is a member of the trithorax group (trxG) that is required for proper expression of Hox genes and is preferentially expressed in haematopoietic stem cells. We have recently reported that ASH1 methylates histone H3 at lysine 36 (K36) but its biological function has remained elusive. Here we show that ASH1 regulates Hox gene expression positively and negatively in a leukemic cell line K562 and is required for myelomonocytic differentiation of murine haematopoietic stem cells. ASH1 binds to endogenous Hox loci in K562 cells and its knockdown causes reduced expression of Hox genes. In addition, ASH1 and MLL1 induce more than 100-fold activation of Hox promoters in HeLa cells if expressed simultaneously but not individually. Notably, ASH1 harbouring a point mutation that kills methyltransferase activity is more efficient than wild type ASH1 in Hox gene activation, indicating that K36 methylation is not a prerequisite for Hox gene expression. Moreover, tethering wild type or catalytically inactive methyltransferase domain of ASH1 to a heterologous promoter causes downregulation or upregulation, respectively, of transcription, supporting a hypothesis that K36 methylation imparts repression. Knockdown of ASH1 in K562 cells in vitro causes increased expression of ε-globin gene and reduced expression of myelomonocytic markers GPIIb and GPIIIa, whereas knockdown of ASH1 in murine haematopoietic stem cells in vivo results in decreased number of macrophages and granulocytes, a phenotype similar to that induced by loss of mll1 function. Taken together, our data suggest that ASH1 and MLL1 synergize in activation of Hox genes and thereby regulate development of myelomonocytic lineages from haematopoietic stem cells.
format	article
author	Yujiro Tanaka Koji Kawahashi Zen-Ichiro Katagiri Yasuhiro Nakayama Milind Mahajan Dimitris Kioussis
author_facet	Yujiro Tanaka Koji Kawahashi Zen-Ichiro Katagiri Yasuhiro Nakayama Milind Mahajan Dimitris Kioussis
author_sort	Yujiro Tanaka
title	Dual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression.
title_short	Dual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression.
title_full	Dual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression.
title_fullStr	Dual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression.
title_full_unstemmed	Dual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression.
title_sort	dual function of histone h3 lysine 36 methyltransferase ash1 in regulation of hox gene expression.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/9055b1051b904f7187a6e8be96043fa6
work_keys_str_mv	AT yujirotanaka dualfunctionofhistoneh3lysine36methyltransferaseash1inregulationofhoxgeneexpression AT kojikawahashi dualfunctionofhistoneh3lysine36methyltransferaseash1inregulationofhoxgeneexpression AT zenichirokatagiri dualfunctionofhistoneh3lysine36methyltransferaseash1inregulationofhoxgeneexpression AT yasuhironakayama dualfunctionofhistoneh3lysine36methyltransferaseash1inregulationofhoxgeneexpression AT milindmahajan dualfunctionofhistoneh3lysine36methyltransferaseash1inregulationofhoxgeneexpression AT dimitriskioussis dualfunctionofhistoneh3lysine36methyltransferaseash1inregulationofhoxgeneexpression
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Dual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression.

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