UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.

Karl Agger; Paul A C Cloos; Jesper Christensen; Diego Pasini; Simon Rose; Juri Rappsilber; Irina Issaeva; Eli Canaani; Anna Elisabetta Salcini; Kristian Helin

doi:10.1038/nature06145

UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.

Karl Agger, Paul A C Cloos, Jesper Christensen, Diego Pasini, Simon Rose, Juri Rappsilber, Irina Issaeva, Eli Canaani, Anna Elisabetta Salcini, Kristian Helin

891 Citations (Scopus)

Abstract

The trithorax and the polycomb group proteins are chromatin modifiers, which play a key role in the epigenetic regulation of development, differentiation and maintenance of cell fates. The polycomb repressive complex 2 (PRC2) mediates transcriptional repression by catalysing the di- and tri-methylation of Lys 27 on histone H3 (H3K27me2/me3). Owing to the essential role of the PRC2 complex in repressing a large number of genes involved in somatic processes, the H3K27me3 mark is associated with the unique epigenetic state of stem cells. The rapid decrease of the H3K27me3 mark during specific stages of embryogenesis and stem-cell differentiation indicates that histone demethylases specific for H3K27me3 may exist. Here we show that the human JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3. Furthermore, we demonstrate that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, we show that UTX directly binds to the HOXB1 locus and is required for its activation. Finally mutation of F18E9.5, a Caenorhabditis elegans JMJD3 orthologue, or inhibition of its expression, results in abnormal gonad development. Taken together, these results suggest that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (ref. 8) supports a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation.

Original language	English
Journal	Nature
Volume	449
Issue number	7163
Pages (from-to)	731-4
Number of pages	3
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature06145
Publication status	Published - 2007

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@article{b5fee220519511dd8d9f000ea68e967b,

title = "UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.",

abstract = "The trithorax and the polycomb group proteins are chromatin modifiers, which play a key role in the epigenetic regulation of development, differentiation and maintenance of cell fates. The polycomb repressive complex 2 (PRC2) mediates transcriptional repression by catalysing the di- and tri-methylation of Lys 27 on histone H3 (H3K27me2/me3). Owing to the essential role of the PRC2 complex in repressing a large number of genes involved in somatic processes, the H3K27me3 mark is associated with the unique epigenetic state of stem cells. The rapid decrease of the H3K27me3 mark during specific stages of embryogenesis and stem-cell differentiation indicates that histone demethylases specific for H3K27me3 may exist. Here we show that the human JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3. Furthermore, we demonstrate that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, we show that UTX directly binds to the HOXB1 locus and is required for its activation. Finally mutation of F18E9.5, a Caenorhabditis elegans JMJD3 orthologue, or inhibition of its expression, results in abnormal gonad development. Taken together, these results suggest that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (ref. 8) supports a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation.",

author = "Karl Agger and Cloos, {Paul A C} and Jesper Christensen and Diego Pasini and Simon Rose and Juri Rappsilber and Irina Issaeva and Eli Canaani and Salcini, {Anna Elisabetta} and Kristian Helin",

note = "Keywords: Animals; Caenorhabditis elegans; Cell Line; Gene Expression Regulation, Developmental; Genes, Homeobox; Gonads; Homeodomain Proteins; Humans; Methylation; Nuclear Proteins; Oxidoreductases, N-Demethylating; RNA Interference; RNA, Messenger; Trans-Activation (Genetics)",

year = "2007",

doi = "10.1038/nature06145",

language = "English",

volume = "449",

pages = "731--4",

journal = "Nature",

issn = "0028-0836",

publisher = "nature publishing group",

number = "7163",

}

TY - JOUR

T1 - UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.

AU - Agger, Karl

AU - Cloos, Paul A C

AU - Christensen, Jesper

AU - Pasini, Diego

AU - Rose, Simon

AU - Rappsilber, Juri

AU - Issaeva, Irina

AU - Canaani, Eli

AU - Salcini, Anna Elisabetta

AU - Helin, Kristian

N1 - Keywords: Animals; Caenorhabditis elegans; Cell Line; Gene Expression Regulation, Developmental; Genes, Homeobox; Gonads; Homeodomain Proteins; Humans; Methylation; Nuclear Proteins; Oxidoreductases, N-Demethylating; RNA Interference; RNA, Messenger; Trans-Activation (Genetics)

PY - 2007

Y1 - 2007

N2 - The trithorax and the polycomb group proteins are chromatin modifiers, which play a key role in the epigenetic regulation of development, differentiation and maintenance of cell fates. The polycomb repressive complex 2 (PRC2) mediates transcriptional repression by catalysing the di- and tri-methylation of Lys 27 on histone H3 (H3K27me2/me3). Owing to the essential role of the PRC2 complex in repressing a large number of genes involved in somatic processes, the H3K27me3 mark is associated with the unique epigenetic state of stem cells. The rapid decrease of the H3K27me3 mark during specific stages of embryogenesis and stem-cell differentiation indicates that histone demethylases specific for H3K27me3 may exist. Here we show that the human JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3. Furthermore, we demonstrate that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, we show that UTX directly binds to the HOXB1 locus and is required for its activation. Finally mutation of F18E9.5, a Caenorhabditis elegans JMJD3 orthologue, or inhibition of its expression, results in abnormal gonad development. Taken together, these results suggest that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (ref. 8) supports a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation.

AB - The trithorax and the polycomb group proteins are chromatin modifiers, which play a key role in the epigenetic regulation of development, differentiation and maintenance of cell fates. The polycomb repressive complex 2 (PRC2) mediates transcriptional repression by catalysing the di- and tri-methylation of Lys 27 on histone H3 (H3K27me2/me3). Owing to the essential role of the PRC2 complex in repressing a large number of genes involved in somatic processes, the H3K27me3 mark is associated with the unique epigenetic state of stem cells. The rapid decrease of the H3K27me3 mark during specific stages of embryogenesis and stem-cell differentiation indicates that histone demethylases specific for H3K27me3 may exist. Here we show that the human JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3. Furthermore, we demonstrate that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, we show that UTX directly binds to the HOXB1 locus and is required for its activation. Finally mutation of F18E9.5, a Caenorhabditis elegans JMJD3 orthologue, or inhibition of its expression, results in abnormal gonad development. Taken together, these results suggest that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (ref. 8) supports a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation.

U2 - 10.1038/nature06145

DO - 10.1038/nature06145

M3 - Journal article

C2 - 17713478

SN - 0028-0836

VL - 449

SP - 731

EP - 734

JO - Nature

JF - Nature

IS - 7163

ER -

UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.

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