Hi-C analysis in TNF-alpha-stimulated human umblical vein endothelial cells (HUVECs)
Ontology highlight
ABSTRACT: Lysine 9 di-methylation and lysine 27 tri-methylation of histone H3 (H3K9me2 and H3K27me3) are mostly linked to gene repression. However, functions of repressive histone methylation dynamics during inflammatory responses remain poorly understood. Here, we show that lysine demethylase 7A (KDM7A) and 6A (UTX) are rapidly transported to nuclear factor kappa-B (NF-κB) related elements in human endothelial cells in response to tumor necrosis factor (TNF)-α. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and cooperatively activate NF-κB dependent inflammatory genes. Furthermore, using both in situ Hi-C and other 3C based technology, loops between super enhancers (SEs) are newly formed following TNF-α-stimuli at NF-κB-dependent inflammatory loci where KDM7A- and UTX-recruitment coincide. Collectively, these findings suggest that erasing of repressive histone marks by KDM7A and UTX within NF-κB-related elements might functionally associate with formation of SE-SE three-dimensional interactions and could be a cue signal during inflammatory responses in human endothelial cells.
Project description:Lysine 9 di-methylation and lysine 27 tri-methylation of histone H3 (H3K9me2 and H3K27me3) are mostly linked to gene repression. However, functions of repressive histone methylation dynamics during inflammatory responses remain poorly understood. Here, we show that lysine demethylase 7A (KDM7A) and 6A (UTX) are rapidly transported to nuclear factor kappa-B (NF-κB) related elements in human endothelial cells in response to tumor necrosis factor (TNF)-α. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and cooperatively activate NF-κB dependent inflammatory genes. Furthermore, using both in situ Hi-C and other 3C based technology, loops between super enhancers (SEs) are newly formed following TNF-α-stimuli at NF-κB-dependent inflammatory loci where KDM7A- and UTX-recruitment coincide. Collectively, these findings suggest that erasing of repressive histone marks by KDM7A and UTX within NF-κB-related elements might functionally associate with formation of SE-SE three-dimensional interactions and could be a cue signal during inflammatory responses in human endothelial cells.
Project description:Lysine 9 di-methylation and lysine 27 tri-methylation of histone H3 (H3K9me2 and H3K27me3) are mostly linked to gene repression. However, functions of repressive histone methylation dynamics during inflammatory responses remain poorly understood. Here, we show that lysine demethylase 7A (KDM7A) and 6A (UTX) are rapidly transported to nuclear factor kappa-B (NF-κB) related elements in human endothelial cells in response to tumor necrosis factor (TNF)-α. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and cooperatively activate NF-κB dependent inflammatory genes. Furthermore, using both in situ Hi-C and other 3C based technology, loops between super enhancers (SEs) are newly formed following TNF-α-stimuli at NF-κB-dependent inflammatory loci where KDM7A- and UTX-recruitment coincide. Collectively, these findings suggest that erasing of repressive histone marks by KDM7A and UTX within NF-κB-related elements might functionally associate with formation of SE-SE three-dimensional interactions and could be a cue signal during inflammatory responses in human endothelial cells.
Project description:Lysine 9 di-methylation and lysine 27 tri-methylation of histone H3 (H3K9me2 and H3K27me3) are mostly linked to gene repression. However, functions of repressive histone methylation dynamics during inflammatory responses remain poorly understood. Here, we show that lysine demethylase 7A (KDM7A) and 6A (UTX) are rapidly transported to nuclear factor kappa-B (NF-κB) related elements in human endothelial cells in response to tumor necrosis factor (TNF)-α. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and cooperatively activate NF-κB dependent inflammatory genes. Furthermore, using both in situ Hi-C and other 3C based technology, loops between super enhancers (SEs) are newly formed following TNF-α-stimuli at NF-κB-dependent inflammatory loci where KDM7A- and UTX-recruitment coincide. Collectively, these findings suggest that erasing of repressive histone marks by KDM7A and UTX within NF-κB-related elements might functionally associate with formation of SE-SE three-dimensional interactions and could be a cue signal during inflammatory responses in human endothelial cells.
Project description:Lysine 9 di-methylation and lysine 27 tri-methylation of histone H3 (H3K9me2 and H3K27me3) are mostly linked to gene repression. However, functions of repressive histone methylation dynamics during inflammatory responses remain poorly understood. Here, we show that lysine demethylase 7A (KDM7A) and 6A (UTX) are rapidly transported to nuclear factor kappa-B (NF-κB) related elements in human endothelial cells in response to tumor necrosis factor (TNF)-α. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and cooperatively activate NF-κB dependent inflammatory genes. Furthermore, using both in situ Hi-C and other 3C based technology, loops between super enhancers (SEs) are newly formed following TNF-α-stimuli at NF-κB-dependent inflammatory loci where KDM7A- and UTX-recruitment coincide. Collectively, these findings suggest that erasing of repressive histone marks by KDM7A and UTX within NF-κB-related elements might functionally associate with formation of SE-SE three-dimensional interactions and could be a cue signal during inflammatory responses in human endothelial cells.
Project description:Lysine 9 di-methylation and lysine 27 tri-methylation of histone H3 (H3K9me2 and H3K27me3) are mostly linked to gene repression. However, functions of repressive histone methylation dynamics during inflammatory responses remain poorly understood. Here, we show that lysine demethylase 7A (KDM7A) and 6A (UTX) are rapidly transported to nuclear factor kappa-B (NF-κB) related elements in human endothelial cells in response to tumor necrosis factor (TNF)-α. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and cooperatively activate NF-κB dependent inflammatory genes. Furthermore, using both in situ Hi-C and other 3C based technology, loops between super enhancers (SEs) are newly formed following TNF-α-stimuli at NF-κB-dependent inflammatory loci where KDM7A- and UTX-recruitment coincide. Collectively, these findings suggest that erasing of repressive histone marks by KDM7A and UTX within NF-κB-related elements might functionally associate with formation of SE-SE three-dimensional interactions and could be a cue signal during inflammatory responses in human endothelial cells.
Project description:Temporal and spatial colinear expression of Hox genes determines the specification of positional identities of the embryo. Post-translational modifications of histones contribute to transcriptional regulation, and are required for proper control of biological processes, including differentiation and development. Lysine demethylase 7A (Kdm7a) demethylates lysine 9 di-methylation of histone H3 (H3K9me2) and participates in transcriptional activation of developmental genes. However, the role of Kdm7a during mouse embryonic development remains to be elucidated. Here, we show that Kdm7a-/- mice exhibit anterior homeotic transformation of the axial skeleton (i.e. an increase in the number of presacral elements). Importantly, posterior Hox genes (caudally from Hox9) are specifically down-regulated in Kdm7a-/- embryos, which correlate with increased levels of H3K9me2. Taken together, these data suggest that Kdm7a is able to control transcription of posterior Hox genes, likely through its demethylating activity, and thereby regulating anterior-posterior development in mice.
Project description:Temporal and spatial colinear expression of Hox genes determines the specification of positional identities of the embryo. Post-translational modifications of histones contribute to transcriptional regulation, and are required for proper control of biological processes, including differentiation and development. Lysine demethylase 7A (Kdm7a) demethylates lysine 9 di-methylation of histone H3 (H3K9me2) and participates in transcriptional activation of developmental genes. However, the role of Kdm7a during mouse embryonic development remains to be elucidated. Here, we show that Kdm7a-/- mice exhibit anterior homeotic transformation of the axial skeleton (i.e. an increase in the number of presacral elements). Importantly, posterior Hox genes (caudally from Hox9) are specifically down-regulated in Kdm7a-/- embryos, which correlate with increased levels of H3K9me2. Taken together, these data suggest that Kdm7a is able to control transcription of posterior Hox genes, likely through its demethylating activity, and thereby regulating anterior-posterior development in mice.
Project description:Lysine demethylase 7A (KDM7A) catalyzes the removal of dimethylation from histone H3 lysine 9 and lysine 27, both of which are associated with transcription repression. Previous study indicated that Kdm7a mRNA in the medial prefrontal cortex (mPFC) increased after drug exposure, yet its role in drug-related behaviors is largely unknown. In a morphine-conditioned place preference (CPP) paradigm, our findings revealed a specific increase of Kdm7a expression in the mPFC seven days after drug withdrawal. Subsequently, our results demonstrated that knockdown of Kdm7a in the mPFC did not affect the acquisition of morphine-induced CPP, but it attenuated memory consolidation. To further explore Kdm7a-mediated transcriptomic changes, we employed Nanopore direct RNA sequencing. Transcriptome profiling unveiled several gene expression alterations impacted by KDM7A, which were enriched in relevant neural function categories. Notably, we identified and validated fascin actin-bundling protein 1 (Fscn1) as a downstream molecular target. Knockdown of Fscn1 had a similar impact on CPP to Kdm7a, along with a corresponding decrease in dendritic spine density in the mPFC. Additionally, ChIP analysis demonstrated that silencing Kdm7a in N2a cells resulted in decreased enrichment of H3K9me2 and H3K27me2 at the Fscn1 promoter region, suggesting that Kdm7a may act as a crucial regulator of transcriptional responses to morphine-related reward memory via Fscn1.
Project description:We describe inactivating somatic mutations in the histone lysine demethylase, UTX, in human cancers pointing to the deregulation of histone H3 lysine methylation in the development of multiple tumour types. Gene expression was analysed on Illumina Human WG-6 v2 BeadChips following standard protocols. Data quality test and normalization were performed using the Lumi package implemented in R.
Project description:Previous studies linked mac activation with the ubiquitination (ub) status of key proteins in inflammatory signal pathways. Lysine-48 ub (K48-ub) of the NF-κB inhibitor (IκB), the final checkpoint of the NFκB pathway, leads to IκB degradation and consequent NF-κB-associated inflammation. In contrast, TRAF6, an upstream positive regulator of the NF-κB pathway, is modulated by K63-ub, leading to its conformational change and activation. However, a comprehensive analysis of ub profiles of polarized macs has not been reported. If a unique ub signature is associated with individual mac subsets is not known.