New insights into the role of Jmjd3 and Utx in axial skeletal formation in mice

Abstract

Jmjd3 and Utx are demethylases specific for lysine 27 of histone H3. Previous reports indicate that Jmjd3 is essential for differentiation of various cell types, such as macrophages and epidermal cells in mice, whereas Utx is involved in cancer and developmental diseases in humans and mice, as well as regulation in zebrafish and nematodes. Here, we report that Jmjd3, but not Utx, is involved in axial skeletal formation in mice. A Jmjd3 mutant embryo (), but not a catalytically inactive Utx truncation mutant (), showed anterior homeotic transformation. Quantitative RT-PCR and microarray analyses showed reduced expression in both embryos and tailbuds, whereas levels of activators, such as Wnt signaling factors and retinoic acid synthases, did not decrease, which suggests that Jmjd3 plays a regulatory role in expression during axial patterning. Chromatin immunoprecipitation analyses of embryo tailbud tissue showed trimethylated lysine 27 on histone H3 to be at higher levels at the loci in mutants compared with wild-type tailbuds. In contrast, trimethylated lysine 4 on histone H3 levels were found to be equivalent in wild-type and tailbuds. Demethylase-inactive Jmjd3 mutant embryos showed the same phenotype as mice. These results suggest that the demethylase activity of Jmjd3, but not that of Utx, affects mouse axial patterning in concert with alterations in gene expression.-Naruse, C., Shibata, S., Tamura, M., Kawaguchi, T., Abe, K., Sugihara, K., Kato, T., Nishiuchi, T., Wakana, S., Ikawa, M., Asano, M. New insights into the role of Jmjd3 and Utx in axial skeletal formation in mice.

Phenotypic integration of the cervical vertebrae in the Hominoidea (Primates)

“…The Hox genes shaping cervical vertebral morphology and number are further regulated by and interacting with other genes, such as Jmjd3, which regulates Hox expression (Naruse et al. ), and the Polycomb genes and ActRIIB and Gdf11, which regulate anterior–posterior and left–right patterning (van der Lugt et al. ; Alkema et al.…”

“…The Hox genes shaping cervical vertebral morphology and number are further regulated by and interacting with other genes, such as Jmjd3, which regulates Hox expression (Naruse et al 2017), and the Polycomb genes and ActRIIB and Gdf11, which regulate anterior-posterior and left-right patterning (van der Lugt et al 1994;Alkema et al 1995;Yu et al 1995;Akasaka et al 1996;Schumacher et al 1996;Oh et al 2002). More specifically within the vertebral column, Pax1 and Pax9 are directly tied to the development of vertebral bodies but not neural arches (Wallin et al 1994;Peters et al 1999) and Uncx4.1 is tied to the development of pedicles and transverse processes (Leitges et al 2000).…”

Lysine demethylase 7a regulates the anterior-posterior development in mouse by modulating the transcription ofHoxgene cluster

“…For example, a mouse with mutation in the Mel18 gene, also known as the polycomb group ring finger 2 gene, exhibits a posteriorizing shift of body axis (e.g., the loss of rib in the thoracic vertebrae and ectopic ribs in the cervical vertebrae) (Akasaka et al, 1996;Suzuki et al, 2002). Furthermore, Jmjd3 mutant mouse, in which the protein's H3K27 demethylation domain is disrupted, exhibits an anterior homeotic transformation (e.g., the gain of rib in the lumbar vertebra), which is associated with the downregulation of Hox genes (Naruse et al, 2017). Hence, although we observed the involvement of H3K9me2 in the transcriptional regulation of Hox genes, we could not rule out the possible association of H3K9me2 with the H3K27me3-mediated repression mechanisms.…”

“…The Kdm7a mutant newborns appeared grossly normal. Considering that epigenetic factors, including histone demethylases, are associated with the anterior-posterior patterning (Hong et al, 2018;Jansz et al, 2018;Naruse et al, 2017;Terranova et al, 2006), we investigated whether Kdm7a plays a role in the animal body patterning. To this end, we generated whole-mount skeletal preparations of postnatal day 1 wild-type and Kdm7a mutant mice.…”

“…On the other hand, jumonji C (JmjC) domain-containing proteins, Utx and Jmjd3, specifically demethylate H3K27me2/3, and are involved in transcriptional activation of the Hox genes (Agger et al, 2007;Lan et al, 2007). Although catalytic action of Utx has been implicated in the regulation of expression of the Hox genes during zebrafish development (Lan et al, 2007), it has been recently demonstrated that mouse with catalytically-inactive Jmjd3, but not an Utx mutant, exhibits anterior homeotic transformation associated with a downregulation of Hox genes (Naruse et al, 2017).…”