Interplay Between BALL and CREB Binding Protein Maintains H3K27 Acetylation on Active Genes in Drosophila.
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ABSTRACT:
SUBMITTER: Shaukat A
PROVIDER: S-EPMC8509297 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The periodontal ligament is a soft connective tissue embedded between the alveolar bone and cementum, the surface hard tissue of teeth. Periodontal ligament fibroblasts (PDLF) actively express osteo/cementogenic genes, which contribute to periodontal tissue homeostasis. However, the key factors maintaining the osteo/cementogenic abilities of PDLF remain unclear. We herein demonstrated that PPARγ was expressed by in vivo periodontal ligament tissue and its distribution pattern correlated with alkaline phosphate enzyme activity. The knockdown of PPARγ markedly reduced the osteo/cementogenic abilities of PDLF in vitro, whereas PPARγ agonists exerted the opposite effects. PPARγ was required to maintain the acetylation status of H3K9 and H3K27, active chromatin markers, and the supplementation of acetyl-CoA, a donor of histone acetylation, restored PPARγ knockdown-induced decreases in the osteo/cementogenic abilities of PDLF. An RNA-seq/ChIP-seq combined analysis identified four osteogenic transcripts, RUNX2, SULF2, RCAN2, and RGMA, in the PPARγ-dependent active chromatin region marked by H3K27ac. Furthermore, RUNX2-binding sites were selectively enriched in the PPARγ-dependent active chromatin region. Collectively, these results identified PPARγ as the key transcriptional factor maintaining the osteo/cementogenic abilities of PDLF and revealed that global H3K27ac modifications play a role in the comprehensive osteo/cementogenic transcriptional alterations mediated by PPARγ.
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Project description:Purpose: Exploring the alteration in histone acetylation colocalized with CREB/CRTC binding, which are important for long-term memory maintenance Methods: The nuclei of Drosophila mushroom bodies were purified and the histone acetylation and CREB/CRTC binding were examined by ChIP-seq using specific antibodies. The sequencing was performed using SOLiD, and aligned to dm3 using Lifescope..The sequence reads that passed quality filters were analyzed by peak calling using PICS and ERD equipped on Strand NGS software. This method using two algorisms excludes false-positive calling of peaks. The PICS and ERD were run using a default setting except for the following parameters; for PICS, 120 bp as an average fragment length, 10 bp as a minimum distance between forward and reverse reads, 200 bp as a minimum distance between forward and reverse reads, 100 bp as a window width, with 5% false discovery rate; for ERD, 2 as an enrichment factor, 100 bp as a window size, 10 bp as a window slide size, 100 bp as a minimum region size. The peaks obtained by ERD analysis were filtered by an enrichment factor of 1.5, and a density of reads at 0.3 for H3K9Ac, 0.15 for H4K16Ac, 0.18 for CREB and 0.15 for CRTC. To determine the histone acetylation-increased sites, the peaks determined from 3 replicates of the trained samples were summed to analyze all peaks. Then the centers of the H3K9Ac and H4K16Ac peaks were extracted, and then used to create neighboring 400 bp windows. The mapped reads were counted in these 400 bp windows for each biological replicate of ChIP-seq analysis. The counted read numbers in individual regions were normalized by elav for H3K9Ac ChIP-seq, and gapdh2 for H4K16Ac ChIP. The normalized read numbers in individual windows obtained from the spaced trained flies and the naïve flies were analyzed by Student’s t test (p < 0.05). Standard deviations of the normalized read numbers in individual windows from 3 replicates of naïve flies were 0.07 in H3K9Ac-ChIP-seq and 0.10 in H4K16Ac-ChIP-seq. Significantly increased peaks showing a more than 1.2-fold increase (>2SD) were determined as sites with an increase in H3K9Ac or H4K16Ac. Results: Using an optimized data analysis workflow, the filtered reads amounted to 12-15 million reads for H3K9Ac in each of 3 replicates, 5-7 million reads for H4K16 in each of 3 replicates, 2.4 million reads for CREB, 2 million reads for CRTC, and 2.9 million reads for input. Using anti-H3K9Ac antibody, we found significant increases in H3K9Ac 1 day after training, and 75.0% of these mapped within 500bps of the transcriptional start sites (TSSs) of 1766 genes. Using anti-H4K16Ac antibody, we found significant increases in H4K16Ac 1 day after spaced training, and 61.6% of these mapped within 500bps of the TSSs of 1320 genes. Epigenetic changes in the vicinity of TSSs suggests that expression of these genes may be increased in LTM maintenance. We also examined CRTC and CREB binding 1 day after training. We identified 2390 CRTC binding sites, of which 79.6% of these were close to CREB binding sites. These CREB/CRTC binding sites mapped to 1394 genes, and were predominately located within 500bp from TSSs (55.4%). Of the 1394 CREB/CRTC target genes, 346 genes showed increases in H3K9Ac, 319 showed increases in H4K16Ac, and 135 showed increases in both. Conclusions: Our study represents the first detailed analysis of chromatin state related to memory in Drosophila mushroom bodied. The optimized data analysis workflows reported here should provide a framework for comparative investigations of tissue-specific epigenetic alterations.
2017-02-09 | GSE73386 | GEO
Project description:Histone post-translational modifications are key gene expression regulators, but their rapid dynamics during development remain difficult to capture. We applied a Fab-based live endogenous modification labeling technique to monitor the changes in histone modification levels during zygotic genome activation (ZGA) in living zebrafish embryos. Among various histone modifications, H3 Lys27 acetylation (H3K27ac) exhibited most drastic changes, accumulating in two nuclear foci in the 64- to 1k-cell-stage embryos. The elongating form of RNA polymerase II, which is phosphorylated at Ser2 in heptad repeats within the C-terminal domain (RNAP2 Ser2ph), and miR-430 transcripts were also concentrated in foci closely associated with H3K27ac. When treated with α-amanitin to inhibit transcription or JQ-1 to inhibit binding of acetyl-reader proteins, H3K27ac foci still appeared but RNAP2 Ser2ph and miR-430 morpholino were not concentrated in foci, suggesting that H3K27ac precedes active transcription during ZGA. We anticipate that the method presented here could be applied to a variety of developmental processes in any model and non-model organisms.
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Project description:The role of cytosine methylation in the structure and function of enhancers is not well understood. In this study, we investigate the role of DNA methylation at enhancers by comparing the epigenomes of the HCT116 cell line and its highly demethylated derivative, DKO1. Unlike promoters, a portion of regular and super- or stretch enhancers show active H3K27ac marks co-existing with extensive DNA methylation, demonstrating the unexpected presence of bivalent chromatin in both cultured and uncultured cells. Furthermore, our findings also show that bivalent regions have fewer nucleosome-depleted regions and transcription factor-binding sites than monovalent regions. Reduction of DNA methylation genetically or pharmacologically leads to a decrease of the H3K27ac mark. Thus, DNA methylation plays an unexpected dual role at enhancer regions, being anti-correlated focally at transcription factor-binding sites but positively correlated globally with the active H3K27ac mark to ensure structural enhancer integrity.
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Project description:Thyroid carcinoma (TC) is the most common endocrine malignancy, and papillary TC (PTC) is the most frequent subtype of TC, accounting for 85-90% of all the cases. Aberrant histone acetylation contributes to carcinogenesis by inducing the dysregulation of certain cancer-related genes. However, the histone acetylation landscape in PTC remains elusive. Here, we interrogated the epigenomes of PTC and benign thyroid nodule (BTN) tissues by applying H3K27ac chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) along with RNA-sequencing. By comparing the epigenomic features between PTC and BTN, we detected changes in H3K27ac levels at active regulatory regions, identified PTC-specific super-enhancer-associated genes involving immune-response and cancer-related pathways, and uncovered several genes that associated with disease-free survival of PTC. In summary, our data provided a genome-wide landscape of histone modification in PTC and demonstrated the role of enhancers in transcriptional regulations associated with prognosis of PTC.
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Project description:BackgroundFetal alcohol exposure affects 1 in 100 children making it the leading cause of mental retardation in the US. It has long been known that alcohol affects cerebellum development and function. However, the underlying molecular mechanism is unclear.Methodology/principal findingsWe demonstrate that CREB binding protein (CBP) is widely expressed in granule and Purkinje neurons of the developing cerebellar cortex of naïve rats. We also show that exposure to ethanol during the 3(rd) trimester-equivalent of human pregnancy reduces CBP levels. CBP is a histone acetyltransferase, a component of the epigenetic mechanism controlling neuronal gene expression. We further demonstrate that the acetylation of both histone H3 and H4 is reduced in the cerebellum of ethanol-treated rats.Conclusions/significanceThese findings indicate that ethanol exposure decreases the expression and function of CBP in the developing cerebellum. This effect of ethanol may be responsible for the motor coordination deficits that characterize fetal alcohol spectrum disorders.
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Project description:Cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-binding protein (CBP) is a histone acetyltransferase that plays a pivotal role in the control of histone modification and the expression of cytokine-encoding genes in inflammatory diseases, including sepsis and lung injury. We found that the E3 ubiquitin ligase subunit FBXL19 targeted CBP for site-specific ubiquitylation and proteasomal degradation. The ubiquitylation-dependent degradation of CBP reduced the extent of lipopolysaccharide (LPS)-dependent histone acetylation and cytokine release in mouse lung epithelial cells and in a mouse model of sepsis. Furthermore, we demonstrated that the deubiquitylating enzyme USP14 (ubiquitin-specific peptidase 14) stabilized CBP by reducing its ubiquitylation. LPS increased the stability of CBP by reducing the association between CBP and FBXL19 and by activating USP14. Inhibition of USP14 reduced CBP protein abundance and attenuated LPS-stimulated histone acetylation and cytokine release. Together, our findings delineate the molecular mechanisms through which CBP stability is regulated by FBXL19 and USP14, which results in the modulation of chromatin remodeling and the expression of cytokine-encoding genes.
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Project description:BackgroundGene order in eukaryotic chromosomes is not random and has been linked to coordination of gene expression, chromatin structure and also recombination rate. The evolution of recombination rate is especially relevant for genes involved in immunity because host-parasite co-evolution could select for increased recombination rate (Red Queen hypothesis). To identify patterns left by the intimate interaction between hosts and parasites, I analysed the genomic parameters of the immune genes from 24 gene families/groups of Drosophila melanogaster.Principal findingsImmune genes that directly interact with the pathogen (i.e. recognition and effector genes) clustered in regions of higher recombination rates. Out of these, clustered effector genes were transcribed fastest indicating that transcriptional control might be one major cause for cluster formation. The relative position of clusters to each other, on the other hand, cannot be explained by transcriptional control per se. Drosophila immune genes that show epistatic interactions can be found at an average distance of 15.44+/-2.98 cM, which is considerably closer than genes that do not interact (30.64+/-1.95 cM).ConclusionsEpistatically interacting genes rarely belong to the same cluster, which supports recent models of optimal recombination rates between interacting genes in antagonistic host-parasite co-evolution. These patterns suggest that formation of local clusters might be a result of transcriptional control, but that in the condensed genome of D. melanogaster relative position of these clusters may be a result of selection for optimal rather than maximal recombination rates between these clusters.
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Project description:As approximately 70% of human breast tumors are estrogen receptor α (ERα)-positive, estrogen and ERα play essential roles in breast cancer development. By interrupting the ERα signaling pathway, endocrine therapy has been proven to be an effective therapeutic strategy. In this study, we identified a mechanism by which Transcription Start Site (TSS)-associated histone H3K27 acetylation signals the Super Elongation Complex (SEC) to regulate transcriptional elongation of the ESR1 (ERα) gene. SEC interacts with H3K27ac on ESR1 TSS through its scaffold protein AFF4. Depletion of AFF4 by siRNA or CRISPR/Cas9 dramatically reduces expression of ESR1 and its target genes, consequently inhibiting breast cancer cell growth. More importantly, a AFF4 mutant which lacks H3K27ac interaction failed to rescue ESR1 gene expression, suggesting H3K27 acetylation at TSS region is a key mark bridging the transition from transcriptional initiation to elongation, and perturbing SEC function can be an alternative strategy for targeting ERα signaling pathway at chromatin level.
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