FUNCTIONAL DISSECTION OF THE HISTONE LYSINE DEMETHYLASE JMJD3

Epigenetic control of developmental genes has emerged as a key mechanism in the acquisition of developmental competence. In particular, patterns of methylation at lysine 4 and 27 of histone H3 have been associated, respectively, with states of gene activation and repression that are developmentally regulated and are thought to underlie the establishment of lineage specific gene expression programs. Recent studies have provided fundamental insight into the problem of lineage specification by comparing global changes in chromatin and transcription between embryonic stem cells (ESCs) and neural stems cells (NSCs), points of departure and arrival for neural commitment, respectively. With these maps of the differentiated state in place, a central task is now to unravel the chromatin dynamics that enable these differentiation transitions between pluripotent ESCs and multipotent NSCs. In particular, the observation that lineage-specific genes repressed in ESCs by Polycomb-mediated histone H3 lysine 27 trimethylation (H3K27me3) are demethylated and derepressed in differentiated cells posited the existence of a H3K27-specific demethylase. In order to gain insight into the epigenetic mechanisms that enable lineage specification, we investigated in the first part of this work the early stages of neural commitment using as a model system the neural differentiation of mouse ESCs. Using a comprehensive expression analysis of JmjC genes, we identified Jmjd3 as a H3K27me3 demethylase that is specifically upregulated at the onset of neural differentiation. This study revealed that Jmjd3 controls the expression of key regulators and markers of neurogenesis and is required for commitment to the neural lineage. In the second part of this work, we have used a genetic loss-of-function approach to characterise the role of Jmjd3 in vivo. Mice lacking Jmjd3 die at birth from respiratory failure. A detailed characterisation of this neurodevelopmental phenotype demonstrated that the defect in respiratory rhythmogenesis upon loss of Jmjd3 is due to an abnormal maturation of the preBötzinger complex (preBötC), one of the two principal sites generating respiratory rhythm in mammals.