The Lysine Demethylase dKDM2 Is Non-essential for Viability, but Regulates Circadian Rhythms in .

Post-translational modification of histones, such as histone methylation controlled by specific methyltransferases and demethylases, play critical roles in modulating chromatin dynamics and transcription in eukaryotes. Misregulation of histone methylation can lead to aberrant gene expression, thereby contributing to abnormal development and diseases such as cancer. As such, the mammalian lysine-specific demethylase 2 (KDM2) homologs, KDM2A and KDM2B, are either oncogenic or tumor suppressive depending on specific pathological contexts. However, the role of KDM2 proteins during development remains poorly understood. Unlike vertebrates, has only one KDM2 homolog (dKDM2), but its functions remain elusive due to the complexities of the existing mutant alleles. To address this problem, we have generated two null alleles using the CRISPR/Cas9 technique. These homozygous mutants are fully viable and fertile, with no developmental defects observed under laboratory conditions. However, the null mutant adults display defects in circadian rhythms. Most of the mutants become arrhythmic under constant darkness, while the circadian period of the rhythmic mutant flies is approximately 1 h shorter than the control. Interestingly, lengthened circadian periods are observed when dKDM2 is overexpressed in circadian pacemaker neurons. Taken together, these results demonstrate that is not essential for viability; instead, dKDM2 protein plays important roles in regulating circadian rhythms in . Further analyses of the molecular mechanisms of dKDM2 and its orthologs in vertebrates regarding the regulation of circadian rhythms will advance our understanding of the epigenetic regulations of circadian clocks.