Abstract
Histone demethylases have emerged as important players in developmental processes. Jumonji domain containing-3 (Jmjd3) has been identified as a key histone demethylase that plays a critical role in the regulation of gene expression; however, the in vivo function of Jmjd3 in embryonic development remains largely unknown. To this end, we generated Jmjd3 global and conditional knockout mice. Global deletion of Jmjd3 induces perinatal lethality associated with defective lung development. Tissue and stage-specific deletion revealed that Jmjd3 is dispensable in the later stage of embryonic lung development. Jmjd3 ablation downregulates the expression of genes critical for lung development and function, including AQP-5 and SP-B. Jmjd3-mediated alterations in gene expression are associated with locus-specific changes in the methylation status of H3K27 and H3K4. Furthermore, Jmjd3 is recruited to the SP-B promoter through interactions with the transcription factor Nkx2.1 and the epigenetic protein Brg1. Taken together, these findings demonstrate that Jmjd3 plays a stage-dependent and locus-specific role in the mouse lung development. Our study provides molecular insights into the mechanisms by which Jmjd3 regulates target gene expression in the embryonic stages of lung development.
Highlights
Gene expression is epigenetically regulated through DNA methylation as well as covalent chromatin modifications such as acetylation, phosphorylation, ubiquitination, sumoylation, and methylation of histones
Jmjd3 deletion causes multiple embryonic defects To study the in vivo functions of Jmjd3 during development, Jmjd3 KO mice were generated by homologous recombination technique [17]
Consistent with this observation, we found that the lungs of Jmjd3-deficient mice were not inflated with air and much smaller in size compared with the lungs of WT mice (Figure 1B)
Summary
Gene expression is epigenetically regulated through DNA methylation as well as covalent chromatin modifications such as acetylation, phosphorylation, ubiquitination, sumoylation, and methylation of histones. Jmjd expression is induced by vitamin D and proinflammatory stimuli in macrophages and is required for the expression of INK4A-ARF, Nodal, and Irf in fibroblasts, mouse embryonic stem cells (ESCs), and macrophages, respectively [12,13,14,15,16]. We showed that Jmjd plays a vital role in induced pluripotent stem cell reprogramming by regulating INK4a/Arf expression and PHF20 degradation [17]. Several studies using Jmjd knockout (KO) mice have demonstrated the importance of Jmjd in differentiation and development in vivo. Jmjd has been shown to play a crucial role in the regulation of macrophage development and differentiation [15] and mesoderm differentiation and cardiovascular lineage commitment in mouse ESCs [18]. The role and mechanism of action of Jmjd in differentiation and developmental processes remain largely unknown
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