H3K36 methylation

Cell type-specific barcoding of genomes requires the establishment of hundreds of heterochromatin domains where heterochromatin-associated repressive complexes hinder chromatin accessibility thereby silencing genes. At heterochromatin-euchromatin borders, regulation of accessibility not only depends on the delimitation of heterochromatin but may also involve interplays with nearby genes and their transcriptional activity, or alternatively on histone modifiers, chromatin barrier insulators, and more global demarcation of chromosomes into 3D compartmentalized domains and topological-associating domain (TADs)...

In Saccharomyces cerevisiae, cryptic transcription at the coding region is prevented by the activity of Sin3 histone deacetylase (HDAC) complex Rpd3S, which is carried by the transcribing RNA polymerase II (RNAPII) to deacetylate and stabilize chromatin. Despite its fundamental importance, the mechanisms by which Rpd3S deacetylates nucleosomes and regulates chromatin dynamics remain elusive. Here, we determined several cryo-EM structures of Rpd3S in complex with nucleosome core particles (NCPs), including the H3/H4 deacetylation states, the alternative deacetylation state, the linker tightening state, and a state in which Rpd3S co-exists with the Hho1 linker histone on NCP...

Eukaryotic transcription is dependent on specific histone modifications. Their recognition by chromatin readers triggers complex processes relying on the coordinated association of transcription regulatory factors. Although various modification states of a particular histone residue often lead to differential outcomes, it is not entirely clear how they are discriminated. Moreover, the contribution of intrinsically disordered regions outside of the specialized reader domains to nucleosome binding remains unexplored...

No abstract text is available yet for this article.

Histone methylation and acetylation play a crucial role in response to developmental cues and environmental changes. Previously, we employed mass spectrometry to identify histone modifications such as H3K27ac and H3K36me3 in the model diatom Phaeodactylum tricornutum , which have been shown to be important for transcriptional activation in animal and plant species. To further investigate their evolutionary implications, we utilized chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) and explored their genome-wide distribution in P...

SET and MYND domain protein 2 (SMYD2) can methylate histone H3 at lysine36 (H3K36) and some non-histone substrates to play a role in tumorigenesis. However, It is unclear how SMYD2 contributes to chronic kidney disease (CKD). Here, AZ505 or LLY507, which could inhibit SMYD2, were used in cisplatin-induced CKD to investigate the effects and possible mechanisms by which they might act. We found that high expression of SMYD2 in cisplatin-induced CKD. However, AZ505 or LLY507 can significantly inhibit its expression, improve renal function injury and fibrosis induced by cisplatin, inhibit the transition of epithelial cells to a fibrogenic phenotype and fibrosis-related proteins, inhibit the expression of Inflammatory Cytokines (such as IL-6 and TNF-α), And inhibit the phosphorylation of pro-fibrosis molecule Smad3 and signal transduction and transcription activator-3 (STAT3) and up-regulated the expression of renal protective factor Smad7...

Methyltransferases regulate transcriptome dynamics during development and aging, as well as in disease. Various methyltransferases have been linked to heart disease, through disrupted expression and activity, and genetic variants associated with congenital heart disease. However, in vivo functional data for many of the methyltransferases in the context of the heart are limited. Here, we used the Drosophila model system to investigate different histone 3 lysine 36 (H3K36) methyltransferases for their role in heart development...

Long-term exposure to arsenic, a common environmental pollutant, can induce various types of liver injury, but the mechanism and treatment measures remains unclear. This study constructed a rat model of arsenic-induce liver injury, with methyl group donor S-adenosylmethionine (SAM) supplementation and Rosa roxburghii Tratt juice intervention, to explore the epigenetic mechanism and intervention method of arsenic-induced liver injury from the perspective of hepatic bile acid metabolism. The results showed that arsenic exposure induced the accumulation of total bile acids (TBA) in the liver and serum of rats, and the abnormalities in liver function and liver histopathology...

The epigenetic mechanisms that maintain differentiated cell states remain incompletely understood. Here we employed histone mutants to uncover a crucial role for H3K36 methylation in the maintenance of cell identities across diverse developmental contexts. Focusing on the experimental induction of pluripotency, we show that H3K36M-mediated depletion of H3K36 methylation endows fibroblasts with a plastic state poised to acquire pluripotency in nearly all cells. At a cellular level, H3K36M facilitates epithelial plasticity by rendering fibroblasts insensitive to TGFβ signals...

No abstract text is available yet for this article.

Experiences have been shown to modulate behavior and physiology of future generations in some contexts, but there is limited evidence for inheritance of associative memory in different species. Here, we trained C. elegans nematodes to associate an attractive odorant with stressful starvation conditions and revealed that this associative memory was transmitted to the F1 progeny who showed odor-evoked avoidance behavior. Moreover, the F1 and the F2 descendants of trained animals exhibited odor-evoked cellular stress responses, manifested by the translocation of DAF-16/FOXO to cells' nuclei...

Nuclear receptor-binding SET-domain protein 1 (NSD1), a methyltransferase that catalyzes H3K36me2, is essential for mammalian development and is frequently dysregulated in diseases, including Sotos syndrome. Despite the impacts of H3K36me2 on H3K27me3 and DNA methylation, the direct role of NSD1 in transcriptional regulation remains largely unknown. Here, we show that NSD1 and H3K36me2 are enriched at cis-regulatory elements, particularly enhancers. NSD1 enhancer association is conferred by a tandem quadruple PHD (qPHD)-PWWP module, which recognizes p300-catalyzed H3K18ac...

Post-translational modifications of histone tails alter chromatin accessibility to regulate gene expression. Some viruses exploit the importance of histone modifications by expressing histone mimetic proteins that contain histone-like sequences to sequester complexes that recognize modified histones. Here we identify an evolutionarily conserved and ubiquitously expressed, endogenous mammalian protein Nucleolar protein 16 (NOP16) that functions as a H3K27 mimic. NOP16 binds to EED in the H3K27 trimethylation PRC2 complex and to the H3K27 demethylase JMJD3...

In head and neck squamous cell carcinoma (HNSCC), a significant proportion of tumors have inactivating mutations in the histone methyltransferase NSD1. In these tumors, NSD1 inactivation is a driver of T cell exclusion from the tumor microenvironment (TME). A better understanding of the NSD1-mediated mechanism regulating infiltration of T cells into the TME could help identify approaches to overcome immununosuppression. Here, we demonstrated that NSD1 inactivation results in lower levels of H3K36 di-methylation and higher levels of H3K27 tri-methylation, the latter being a known repressive histone mark enriched on the promoters of key T cell chemokines CXCL9 and CXCL10...

BACKGROUND: Cellular free Zn2+ concentrations ([Zn2+ ]) are primarily coordinated by Zn2+ -transporters, although their roles are not well established in cardiomyocytes. Since we previously showed the important contribution of a Zn2+ -transporter ZnT7 to [Zn2+ ]i regulation in hyperglycemic cardiomyocytes, here, we aimed to examine a possible regulatory role of ZnT7 not only on [Zn2+ ]i but also both the mitochondrial-free Zn2+ and/or Ca2+ in cardiomyocytes, focusing on the contribution of its overexpression to the mitochondrial function...

Protein lysine methyltransferases (PKMTs) play essential roles in gene expression regulation and cancer development. Somatic mutations in PKMTs are frequently observed in cancer cells. In biochemical experiments, we show here that the NSD1 mutations Y1971C, R2017Q and R2017L observed mostly in solid cancers are catalytically inactive suggesting that NSD1 acts as tumor suppressor gene in these tumors. In contrast, the frequently observed T1150A in NSD2 and its T2029A counterpart in NSD1, both observed in leukemia, are hyperactive and introduce up to thee methyl groups in H3K36 in biochemical and cellular assays, while wildtype NSD2 and NSD1 only introduce up to two methyl groups...

Histone modifications are one of the many key mechanisms that regulate gene expression. Ash1 is a histone H3K36 methyltransferase and is involved in gene activation. Ash1 forms a large complex with Mrg15 and Caf1/p55/Nurf55/RbAp48 (AMC complex). The Ash1 subunit alone exhibits very low activity due to the autoinhibition, and the binding of Mrg15 releases the autoinhibition. Caf1 is a scaffolding protein commonly found in several chromatin modifying complexes and has two histone binding pockets: one for H3 and the other for H4...

During postnatal development, the DNA methyltransferase DNMT3A deposits high levels of non-CG cytosine methylation in neurons. This methylation is critical for transcriptional regulation, and loss of this mark is implicated in DNMT3A-associated neurodevelopmental disorders (NDDs). Here, we show in mice that genome topology and gene expression converge to shape histone H3 lysine 36 dimethylation (H3K36me2) profiles, which in turn recruit DNMT3A and pattern neuronal non-CG methylation. We show that NSD1, an H3K36 methyltransferase mutated in NDD, is required for the patterning of megabase-scale H3K36me2 and non-CG methylation in neurons...

Histone methylation plays a vital role in retinal development. However, the role of histone H3K36 methylation in retinal development is not clear. We examined the role of H3K36 methylation by loss-of-function analysis of H3K36me1/2 demethylases, Fbxl10, and Fbxl11. We analyzed the effect of knockout of these genes in the developing and mature retina on retinal development. Knockout of Fbxl10 specifically in the developing retina did not result in gross developmental abnormalities. Although adult rod photoreceptor-specific knockout of Fbxl11 in mature retinas did not result in morphological abnormalities, Fbxl11 knockout in developing retinas increased apoptosis, suppressed the proliferation of retinal progenitor cells, and resulted in microphthalmia...

NSD3/WHSC1L1 lysine methyltransferase promotes the transcription of target genes through di- or tri-methylation at histone H3K36 using SAM as a cofactor. Genetic alterations such as amplification and gain-of-function mutation of NSD3 act as oncogenic drivers in several cancers including squamous cell lung cancer and breast cancer. NSD3 is an important therapeutic target for cancers, but the reported NSD3 inhibitors targeting the catalytic SET domain are very rare and show a poor activity. Herein, from a virtual library screening and the subsequent medicinal chemistry optimization, we identified a novel class of NSD3 inhibitors...