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Dev Biol. 2014 Feb 15;386(2):395-407. doi: 10.1016/j.ydbio.2013.12.016. Epub 2013 Dec 19.

Reduced Euchromatin histone methyltransferase 1 causes developmental delay, hypotonia, and cranial abnormalities associated with increased bone gene expression in Kleefstra syndrome mice.

Author information

1
Department of Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
2
Department of Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Advance Centre of Biomedical Sciences, King Edward Medical University, Lahore, Pakistan.
3
Department of Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
4
Department of Rheumatology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
5
Department of Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
6
Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
7
Department of Biomaterials, Dentistry, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
8
Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
9
Department of Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Molecular Developmental Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
10
Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: i.vanderzee@ncmls.ru.nl.

Abstract

Haploinsufficiency of Euchromatin histone methyltransferase 1 (EHMT1), a chromatin modifying enzyme, is the cause of Kleefstra syndrome (KS). KS is an intellectual disability (ID) syndrome, with general developmental delay, hypotonia, and craniofacial dysmorphisms as additional core features. Recent studies have been focused on the role of EHMT1 in learning and memory, linked to the ID phenotype of KS patients. In this study we used the Ehmt1(+/-) mouse model, and investigated whether the core features of KS were mimicked in these mice. When comparing Ehmt1(+/-) mice to wildtype littermates we observed delayed postnatal growth, eye opening, ear opening, and upper incisor eruption, indicating a delayed postnatal development. Furthermore, tests for muscular strength and motor coordination showed features of hypotonia in young Ehmt1(+/-) mice. Lastly, we found that Ehmt1(+/-) mice showed brachycephalic crania, a shorter or bent nose, and hypertelorism, reminiscent of the craniofacial dysmorphisms seen in KS. In addition, gene expression analysis revealed a significant upregulation of the mRNA levels of Runx2 and several other bone tissue related genes in P28 Ehmt1(+/-) mice. Runx2 immunostaining also appeared to be increased. The mRNA upregulation was associated with decreased histone H3 lysine 9 dimethylation (H3K9me2) levels, the epigenetic mark deposited by Ehmt1, in the promoter region of these genes. Together, Ehmt1(+/-) mice indeed recapitulate KS core features and can be used as an animal model for Kleefstra syndrome. The increased expression of bone developmental genes in the Ehmt1(+/-) mice likely contributes to their cranial dysmorphisms and might be explained by diminished Ehmt1-induced H3K9 dimethylation.

KEYWORDS:

Col11a; Col22a; Dimethylation; Dmp1; Ehmt1; Ehmt1 heterozygous knockout mice; G9a-like protein; GLP; H3K9; KMT1D; Postnatal development; Runx2; Skull and nose bone; mRNA

PMID:
24362066
DOI:
10.1016/j.ydbio.2013.12.016
[Indexed for MEDLINE]
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