Histone demethylase JMJD3 is required for osteoblast differentiation in mice

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Abstract

JMJD3 (KDM6B) is an H3K27me3 demethylases and emerges as an important player in developmental processes. Although some evidence indicated the involvement of JMJD3 in osteoblast differentiation in vitro, its role as a whole in osteoblast differentiation and bone formation in vivo remains unknown. Here we showed that homozygous deletion of Jmjd3 resulted in severe delay of osteoblast differentiation and bone ossification in mice. By biochemical and genetical methods, we demonstrated that JMJD3 mediated RUNX2 transcriptional activity and cooperated with RUNX2 to promote osteoblast differentiation and bone formation in vivo. These results strongly demonstrated that JMJD3 is required for osteoblast differentiation and bone formation in mice.

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

Karl Agger, Paul A C Cloos, Jesper Christensen … (2007)

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.

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Disorders of bone remodeling.

Xu Feng, Jay McDonald (2011)

The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms.

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Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases.

Sunhwa Hong, Young-Wook Cho, Li-Rong Yu … (2007)

Covalent modifications of histones, such as acetylation and methylation, play important roles in the regulation of gene expression. Histone lysine methylation has been implicated in both gene activation and repression, depending on the specific lysine (K) residue that becomes methylated and the state of methylation (mono-, di-, or trimethylation). Methylation on K4, K9, and K36 of histone H3 has been shown to be reversible and can be removed by site-specific demethylases. However, the enzymes that antagonize methylation on K27 of histone H3 (H3K27), an epigenetic mark important for embryonic stem cell maintenance, Polycomb-mediated gene silencing, and X chromosome inactivation have been elusive. Here we show the JmjC domain-containing protein UTX (ubiquitously transcribed tetratricopeptide repeat, X chromosome), as well as the related JMJD3 (jumonji domain containing 3), specifically removes methyl marks on H3K27 in vitro. Further, the demethylase activity of UTX requires a catalytically active JmjC domain. Finally, overexpression of UTX and JMJD3 leads to reduced di- and trimethylation on H3K27 in cells, suggesting that UTX and JMJD3 may function as H3K27 demethylases in vivo. The identification of UTX and JMJD3 as H3K27-specific demethylases provides direct evidence to indicate that similar to methylation on K4, K9, and K36 of histone H3, methylation on H3K27 is also reversible and can be dynamically regulated by site-specific histone methyltransferases and demethylases.

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Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 25 August 2015

Publication date Collection: 2015

Volume: 5

Electronic Location Identifier: 13418

Affiliations

[1 ]Department of Pathology, State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University , Changle West Road, No. 169, Xi’an, 710032, China

[2 ]State Key Laboratory of Molecular Biology, Shanghai Key laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , 320 Yueyang Road, Shanghai, 200031, China

[3 ]Department of Genetics and Development, College of Physicians and Surgeons, Columbia University , New York, NY 10032, USA

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[a ] cdchen@ 123456sibcb.ac.cn

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Publisher Item ID: srep13418

DOI: 10.1038/srep13418

PMC ID: 4548232

PubMed ID: 26302868

SO-VID: cd00baa9-b870-406e-a947-0b3fdd84fbb8

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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

History

Date received : 08 April 2015

Date accepted : 27 July 2015

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Histone demethylase JMJD3 is required for osteoblast differentiation in mice

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

Disorders of bone remodeling.

Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases.

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