TGM2-Mediated Histone Transglutamination is Dictated by Steric Accessibility
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA817606 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18352950_1.fastq.gz | Fastqsanger.gz | |||
| SRR18352950_2.fastq.gz | Fastqsanger.gz | |||
| SRR18352951_1.fastq.gz | Fastqsanger.gz | |||
| SRR18352951_2.fastq.gz | Fastqsanger.gz | |||
| SRR18352952_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 14 |
Similar Datasets
Project description:Histone monoaminylation is a new class of chromatin post-translational modification whereby glutamines are transamidated by tissue transglutaminase 2 (TGM2). Initial studies of these marks have identified serotonylation and dopaminylation on H3Q5, suggesting the modification is a marker of active chromatin. However, little work has been conducted to understand the regulation of TGM2-mediated monoaminylation of chromatin. Here, we employed a highly sensitive TGM2 assay using the small molecule biotin-cadaverine as an acyl-acceptor substrate. In doing so, we discovered that, in addition to H3Q5, H3Q19 and H2A.ZQ123 and Q124 are glutaminyl substrates for TGM2 in vitro. Modification of these residues occurs in a sequence independent manner, with the primary determining factor for substrate selectivity being steric accessibility. We demonstrated that moving substrate glutamines near the histone fold domain turns them into non-substrates. Furthermore, we found that steric accessibility of glutamines appears to be controlled by higher order chromatin structures. Using nucleosome arrays as substrates, we successfully showed that formation of chromatin fibers in vitro reduces levels of monoaminylation. We then successfully extended these findings to a cell based system, showing that TGM2 is not enriched in heterochromatin and that H3Q5 serotonylation and H3K9me3 are mutually exclusive marks. In total, our results strongly suggest that TGM2, and monoaminylation, are excluded from heterochromatin based on steric accessibility
2022-10-05 | GSE198978 | GEO
Project description:Recent studies have identified serotonylation of glutamine-5 on histone H3 (H3Q5ser) as a novel posttranslational modification (PTM) associated with active transcription. While H3Q5ser is known to be installed by tissue transglutaminase 2 (TGM2), the substrate characteristics affecting deposition of the mark, at the level of both chromatin and individual nucleosomes, remain poorly understood. Here, we show that histone serotonylation is excluded from constitutive heterochromatic regions in mammalian cells. Biochemical studies reveal that the formation of higher-order chromatin structures associated with heterochromatin impose a steric barrier that is refractory to TGM2-mediated histone monoaminylation. A series of structure-activity relationship studies, including the use of DNA-barcoded nucleosome libraries, shows that steric hindrance also steers TGM2 activity at the nucleosome level, restricting monoaminylation to accessible sites within histone tails. Collectively, our data indicate that the activity of TGM2 on chromatin is dictated by substrate accessibility rather than by primary sequence determinants or by the existence of preexisting PTMs, as is the case for many other histone-modifying enzymes.
| S-EPMC9618071 | biostudies-literature
Project description:Histone H3 monoaminylations at glutamine(Q) 5 represent important epigenetic markers in neurons that play critical roles in the mediation of permissive gene expression. We previously demonstrated that H3Q5 serotonylation(ser) and dopaminylation(dop) are catalyzed by the Transglutaminase 2 (TGM2) enzyme. Here, we identified a new class of histone monoaminylation, H3Q5 histaminylation(his), which displayed dynamic diurnal expression in brain and contributed to neural rhythmicity. We found that H3Q5his, unlike H3Q5ser, electrostatically inhibited recruitment of the “reader” protein WDR5 and attenuated MLL1 methyltransferase activity on H3 lysine(K) 4. We determined that H3Q5 monoaminylation dynamics are dictated by local monoamine concentrations, which are sensed by TGM2. This noncanonical mechanism indicated that histone monoaminylations can be established and removed by a single enzyme based upon its sensing of cellular microenvironments.
2022-12-06 | GSE209834 | GEO
Project description:Histone H3 monoaminylations at glutamine(Q) 5 represent an important family of epigenetic markers in neurons that play critical roles in the mediation of permissive gene expression (1, 2). We previously demonstrated that H3Q5 serotonylation(ser) and dopaminylation(dop) are catalyzed by the Transglutaminase 2 (TGM2) enzyme and alter both local and global chromatin states (3, 4). Here, we found that TGM2 additionally functions as an “eraser” of H3 monoaminylations that is capable of “re-writing” these epigenetic marks in cells, including a new class of this modification, H3Q5 histaminylation(his), which displays dynamic diurnal expression in brain and contributes to neural rhythmicity. We found that H3Q5his inhibits binding of the MLL1 complex to the H3 N-terminus and attenuates its methyltransferase activity on H3 lysine(K) 4. We determined that H3Q5 monoaminylation dynamics are dictated by local monoamine concentrations, which are utilized by TGM2. Taken together, we present here a novel mechanism through which a single chromatin regulatory enzyme is capable of sensing chemical microenvironments to affect the epigenetic states of cells.
2024-10-10 | PXD053788 | Pride
Project description:Histone H3 monoaminylations at glutamine(Q) 5 represent an important family of epigenetic markers in neurons that play critical roles in the mediation of permissive gene expression (1, 2). We previously demonstrated that H3Q5 serotonylation(ser) and dopaminylation(dop) are catalyzed by the Transglutaminase 2 (TGM2) enzyme and alter both local and global chromatin states (3, 4). Here, we found that TGM2 additionally functions as an “eraser” of H3 monoaminylations that is capable of “rewriting” these epigenetic marks in cells, including a new class of this modification, H3Q5 histaminylation(his), which displays dynamic diurnal expression in brain and contributes to neural rhythmicity. We found that H3Q5his inhibits binding of the MLL1 complex to the H3 N-terminus and attenuates its methyltransferase activity on H3 lysine(K) 4. We determined that H3Q5 monoaminylation dynamics are dictated by local monoamine concentrations, which are utilized by TGM2. Taken together, we present here a novel mechanism through which a single chromatin regulatory enzyme is capable of sensing chemical microenvironments to affect the epigenetic states of cells.
2024-10-10 | PXD053429 | Pride
Project description:Hepatocellular carcinoma (HCC) is a formidable malignancy with limited effective therapeutic avenues. This study was designed to investigate the role of transglutaminase 2 (TGM2) in promoting HCC progression and assess its potential as a target for therapeutic intervention in HCC treatment.TMG2 expression was positively related to a higher AFP level, poor differentiation, and a later BCLC stage. Tgm2 deficiency or H3Q5ser inhibition notably restrained HCC progression. Mechanism research revealed that TGM2-mediated H3Q5ser modifications promote HCC progression via MYC pathway signaling. Furthermore, transcriptional intermediary factor 1 beta (TIF1-β/TRIM28) mediated the recruitment of TGM2 by MYC to facilitate H3Q5ser modifications on MYC targets. Finally, targeting the TGM2 transglutaminase activity significantly suppressed HCC progression in preclinical models.
2024-12-16 | GSE283278 | GEO
Project description:Hepatocellular carcinoma (HCC) is a formidable malignancy with limited effective therapeutic avenues. This study was designed to investigate the role of transglutaminase 2 (TGM2) in promoting HCC progression and assess its potential as a target for therapeutic intervention in HCC treatment.TMG2 expression was positively related to a higher AFP level, poor differentiation, and a later BCLC stage. Tgm2 deficiency or H3Q5ser inhibition notably restrained HCC progression. Mechanism research revealed that TGM2-mediated H3Q5ser modifications promote HCC progression via MYC pathway signaling. Furthermore, transcriptional intermediary factor 1 beta (TIF1-β/TRIM28) mediated the recruitment of TGM2 by MYC to facilitate H3Q5ser modifications on MYC targets. Finally, targeting the TGM2 transglutaminase activity significantly suppressed HCC progression in preclinical models.
2024-12-16 | GSE283279 | GEO
Project description:The PI3K-AKT-mTOR pathway is commonly dysregulated in cancer. Rapalogs exhibit modest clinical benefit likely due to their lack of effects on 4E-BP1. We hypothesized that bi-steric mTORC1-selective inhibitors would have greater potential for clinical benefit than rapalogs in tumors with mTORC1 dysfunction. We assessed this hypothesis in tumor models with high mTORC1 activity both in vitro and in vivo. Bi-steric inhibitors had strong growth inhibition, eliminated phosphorylated 4EBP1, and induced more apoptosis than rapamycin or MLN0128. Multi-omic analysis showed extensive effects of the bi-steric inhibitors in comparison to rapamycin. De novo purine synthesis was markedly and selectively inhibited by bi-sterics through reduction in JUN and its downstream target PRPS1 and appeared to be the cause of apoptosis. Hence, bi-steric mTORC1-selective inhibitors are a novel therapeutic strategy to treat tumors driven by mTORC1 hyperactivation.
2023-11-08 | GSE236742 | GEO
Project description:PIWI-interacting RNAs (piRNAs) mediate transposable element (TE) silencing at the transcriptional or post-transcriptional level in animal gonads. In the Drosophila ovary, Piwiâ??piRNA complexes (Piwiâ??piRISCs) repress TE transcription by modifying the chromatin state, such as H3K9me3 marks. Here, we demonstrate that Piwi physically interacts with linker histone H1. Depletion of Piwi decreases H1 density on target loci, leading to TE derepression. Loss of H1 results in gain of chromatin accessibility at target loci without affecting H3K9me3 and heterochromatin protein 1a (HP1a) density at the same loci. Piwi-mediated TE silencing also requires HP1a by regulating chromatin accessibility through its association with target loci. Thus, Piwiâ??piRISCs require both H1 and HP1a to repress TEs, and the silencing is correlated with the state of chromatin formation rather than H3K9me3 marks. These findings suggest that Piwiâ??piRISCs regulate the interaction of chromatin components with target loci to maintain silencing of the TE state through the modulation of chromatin accessibility. RNA levels, H1 and H3K9me3 occupancy, chromatin accessibility, and Piwi-associated small RNA levels in ovarian somatic cells (OSC) depleted of piRNA pathway components and H1.
2016-06-30 | E-GEOD-81434 | biostudies-arrayexpress
Project description:Decoding changes in chromatin accessibility mediated by KDM6 histone demethylases [ATAC-seq]
| PRJNA926972 | ENA