KANKI, Y. | Search bioRxiv

bioRxiv2019

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

Temporal and spatial colinear expression of the Hox genes determines the specification of positional identities during vertebrate development. Post-translational modifications of histones contribute to transcriptional regulation. Lysine demethylase 7A (Kdm7a) demethylates lysine 9 di-methylation of histone H3 (H3K9me2) and participates in the transcriptional activation of developmental genes. However, the role of Kdm7a during mouse embryonic development remains to be elucidated. Here, we show that Kdm7a-/- mouse exhibits an anterior homeotic transformation of the axial skeleton, including an increased number of presacral elements. Importantly, posterior Hox genes (caudally from Hox9) are specifically downregulated in the Kdm7a-/- embryo, which correlates with increased levels of H3K9me2. These observations suggest that Kdm7a controls the transcription of posterior Hox genes, likely via its demethylating activity, and thereby regulating the murine anterior-posterior development. Such epigenetic regulatory mechanisms may be harnessed for the proper control of coordinate body patterning in vertebrates.

molecular biology↗

bioRxiv2018

Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells

Lysine 9 di-methylation and lysine 27 tri-methylation of histone H3 (H3K9me2 and H3K27me3) are generally linked to gene repression. However, the functions of repressive histone methylation dynamics during inflammatory responses remain enigmatic. We found that tumor necrosis factor (TNF)- rapidly induces the co-occupancy of lysine demethylases 7A (KDM7A) and 6A (UTX) with nuclear factor kappa-B (NF-{kappa}B) recruited elements in human endothelial cells. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and both are required for activation of NF-{kappa}B-dependent inflammatory genes. Chromosome conformation capture-based methods demonstrated increased interactions between TNF--induced super enhancers at NF-{kappa}B-relevant loci, coinciding with KDM7A- and UTX-recruitment. Simultaneous inhibition of KDM7A and UTX significantly reduced leukocyte adhesion in mice, establishing the biological and potential translational relevance of this mechanism. Collectively, these findings suggest that rapid erasure of repressive histone marks by KDM7A and UTX is essential for NF-{kappa}B-dependent regulation of genes that control inflammatory responses of endothelial cells.\n\nHIGHLIGHTSO_LIKDM7A and UTX cooperatively control NF-{kappa}B-dependent transcription in vascular endothelial cells.\nC_LIO_LIDemethylation of repressive histone marks by KDM7A and UTX is critical for early inflammatory responses.\nC_LIO_LIKDM7A and UTX are associated with TNF--induced looping of super enhancers.\nC_LIO_LIPharmacological inhibition of KDM7A and UTX reduces leukocyte adhesive interactions with endothelial cells in mice.\nC_LI

molecular biology↗