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H3K36me3 Modification by SETD2 is Essential for Col11a2 and Sema3e Transcription to Maintain Dentinogenesis in Mice

ABSTRACT: Dentin is a major mineralized component of teeth generated by odontoblasts. Several types of histone methylation have been reported to play important roles in odontoblast differentiation and dentinogenesis. However, the role of methylation on histone 3 at lysine 36 (H3K36) remains enigmatic. Here we find a high expression of SETD2, a methyltransferase catalyzing the trimethylation of H3K36 (H3K36me3), in the odontoblast layer. In vitro knockdown experiments and in vivo observations of two conditional knockout mouse models reveal SETD2 is essential for odontoblast differentiation and dentinogenesis. Integrated analyses of RNA sequencing and Spike-in Cleavage Under Targets and Tagmentation sequencing data show SETD2 is crucial for both H3K36me3 occupancy on the loci of Col11a2 and Sema3e and their transcription. Further experiments verify COL11A2 and SEMA3E act upstream of AKT1 signaling, promoting odontoblastic differentiation. In vitro and in vivo activation of AKT1 using SC79 (an AKT activator) partially rescues the impaired odontoblast differentiation caused by Setd2 knockdown or deficiency. Therefore, our findings indicate that H3K36me3 mediated by SETD2 is essential for dentinogenesis through regulating the expression of Col11a2 and Sema3e and AKT1 signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE288310 | GEO | 2025/02/03

REPOSITORIES: GEO

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H3K36me3 Modification by SETD2 is Essential for Col11a2 and Sema3e Transcription to Maintain Dentinogenesis in Mice

Project description:Dentin is a major mineralized component of teeth generated by odontoblasts. Several types of histone methylation have been reported to play important roles in odontoblast differentiation and dentinogenesis. However, the role of methylation on histone 3 at lysine 36 (H3K36) remains enigmatic. Here we find a high expression of SETD2, a methyltransferase catalyzing the trimethylation of H3K36 (H3K36me3), in the odontoblast layer. In vitro knockdown experiments and in vivo observations of two conditional knockout mouse models reveal SETD2 is essential for odontoblast differentiation and dentinogenesis. Integrated analyses of RNA sequencing and Spike-in Cleavage Under Targets and Tagmentation sequencing data show SETD2 is crucial for both H3K36me3 occupancy on the loci of Col11a2 and Sema3e and their transcription. Further experiments verify COL11A2 and SEMA3E act upstream of AKT1 signaling, promoting odontoblastic differentiation. In vitro and in vivo activation of AKT1 using SC79 (an AKT activator) partially rescues the impaired odontoblast differentiation caused by Setd2 knockdown or deficiency. Therefore, our findings indicate that H3K36me3 mediated by SETD2 is essential for dentinogenesis through regulating the expression of Col11a2 and Sema3e and AKT1 signaling.

2025-02-03 | GSE288311 | GEO

H3K36me3 Modification by SETD2 is Essential for Col11a2 and Sema3e Transcription to Maintain Dentinogenesis in Mice

Project description:H3K36me3 Modification by SETD2 is Essential for Col11a2 and Sema3e Transcription to Maintain Dentinogenesis in Mice

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H3K36me3 Modification by SETD2 is Essential for Col11a2 and Sema3e Transcription to Maintain Dentinogenesis in Mice

Project description:H3K36me3 Modification by SETD2 is Essential for Col11a2 and Sema3e Transcription to Maintain Dentinogenesis in Mice

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H3K36me3 ChIP profiles of Setd2 fl/fl BMSCs infected with lentivirus expressing GFP and Cre

Project description:During the aging process, bone marrow mesenchymal stem cells (BMSCs) exhibit declined osteogenesis accompanied by excess adipogenesis, which will lead to osteoporosis. Here we report that the H3K36 trimethylation, catalyzed by histone methyltransferase SETD2 regulates lineage commitment of BMSCs. Deletion of Setd2 in mBMSCs, through conditional Cre expression driven by Prx1 promoter, resulted in bone loss and marrow adiposity. Loss of Setd2 in BMSCs in vitro facilitated differentiation propensity to adipocytes rather than to osteoblasts. Through conjoint analysis of RNA-seq and ChIP-seq data, we identified a SETD2 functional target gene, Lbp, on which H3K36me3 was enriched, and its expression was affected by Setd2 deficiency. Furthermore, overexpression of LBP could partially rescue the lack of osteogenesis and enhanced adipogenesis resulted from the absence of Setd2 in BMSCs. Further mechanism study demonstrated that the trimethylation level of H3K36 could regulate Lbp transcriptional initiation and elongation. These findings suggest that H3K36 trimethylation mediated by SETD2 could regulate the cell fate of mesenchymal stem cells in vitro and in vivo, indicating that the regulation of H3K36me3 level by targeting SETD2 and/or the administration of downstream LBP protein may represent potential therapeutic way for new treatment in metabolic bone diseases, such as osteoporosis.

2018-11-08 | GSE120351 | GEO

Gene expression profiles of Setd2 fl/fl BMSCs infected with lentivirus expressing GFP and Cre respectively

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A GPI-anchored protein Lypd1 regulates odontoblast differentiation in tooth development

Project description:Lipid rafts are membrane microdomains rich in cholesterol, sphingolipids, glycosylphosphatidylinositol-anchored proteins (GPI-APs), and receptors. They are localized at the plasma membrane and are essential for signal transmission and organogenesis. However, few reports on the specific effects of lipid rafts on organogenesis have been reported. Here, we focused on the odontoblast differentiation that secretes the dentin matrix and generates dentin. We found the GPI-AP, lymphocyte antigen-6 (Ly6)/Plaur domain-containing1 (Lypd1), specifically expressed in the dental papilla, especially preodontoblasts, using single-cell RNA sequence (scRNA-seq). Depletion experiments of lipid rafts and Lypd1 using ex vivo culture and cell cultures showed that differentiation of tooth germ and dental mesenchymal cells was inhibited. Furthermore, the C-terminal structural domain containing the omega site, which is necessary to localize the plasma membrane, of Lypd1 is necessary for odontoblast differentiation and the morphological change like odontoblasts. Stimulating downstream Bone morphogenetic protein (Bmp) signaling by BMP2 caused it to activate the phosphorylation of Smad1/5/8 and promote the expression of odontoblast differentiation markers such as Pannexin 3 (Panx3), Alkaline phosphatase (Alp), and Dentin sialophosphoprotein (Dspp). In contrast, suppression of Lypd1 inhibited the phosphorylation of Smad1/5/8. In addition, the expression of Lypd1 predates any other marker of odontoblast differentiation previously described. That implies that Lypd1 could be employed as a novel earlier differentiation marker of odontoblasts. These results suggest that Lypd1 as GPI-AP of lipid rafts is important for tooth organogenesis and plays a pivotal role in odontoblast differentiation by regulating phosphorylation of Smad1/5/8.

2023-08-25 | GSE206135 | GEO

Comparison of gene expression pattern between Wild-type and Setd2 knockout mESCs [Affymetrix]

Project description:SETD2/HYPB has been known as a histone H3K36 specific methyltransferase. However, its roles in physiology such as development and cellular function remain unclear. In this study, using mESCs as cellular model, we show that Setd2 mainly regulates differentiation of murine embryonic stem cells (mESCs) towards primitive endoderm. This study aimed at exploring how did Setd2 regulate primitive endoderm. differentiation. We used microarrays to detail the global programme of gene expression controled by setd2, which is required for endoderm differentiation. Wild type and Setd2 knockout mESCs were selected for RNA extraction and hybridization on Affymetrix GeneChip® mouse genome 430 2.0 arrays. We sought to obtain some deregulated genes, which were required for primitive endoderm differentiation. For comparison, three biological repeats of each were performed.

2014-10-14 | E-GEOD-54931 | biostudies-arrayexpress

Odontoblast-like cells and dental pulp fibroblasts stimulated with LTA, poly(I:C) and LPS.

Project description:Odontoblasts and fibroblasts are suspected to influence the innate immune response triggered in the dental pulp by micro-organisms that progressively invade the human tooth during the carious process. To determine whether they differ in their responses to oral pathogens, we performed a systematic comparative analysis of odontoblast-like cell and pulp fibroblast responses to TLR2, TLR3 and TLR4 specific agonists (lipoteichoic acid [LTA], double-stranded RNA and lipopolysaccharide [LPS], respectively). Cells responded to these agonists by differential up-regulation of chemokine gene expression. CXCL2 and CXCL10 were thus increased by LTA only in odontoblast-like cells, while LPS increased CCL7, CCL26 and CXCL11 only in fibroblasts. These data suggest that odontoblasts and pulp fibroblasts differ in their innate immune responses to oral micro-organisms that invade the pulp tissue. Keywords: cell type comparaison Dental pulp fibroblasts and Odontoblast-like cells stimulated with lipopolysaccharide, ipoteichoic acid or poly(I:C), or unstimulated. Triplicates.

2010-06-25 | E-GEOD-9560 | biostudies-arrayexpress

Chromatin landscape analysis of ccRCC cell line upon SETD2 rescue [ATACseq_JHRCC12]

Project description:SETD2, a H3K36 trimethyltransferase, is frequently mutated in human cancers with the highest prevalence (13%) in clear cell renal cell carcinoma (ccRCC). Genomic profiling of primary ccRCC tumors reveals a positive correlation between SETD2 mutations and metastasis. However, whether and how SETD2-loss promotes metastasis remains unclear. Here, we detected SETD2 mutations in 24 of 51 (47%) metastatic ccRCC tumors. Using SETD2-mutant metastatic ccRCC patient-derived cell line and xenograft models, we showed that H3K36me3 restoration greatly reduced distant metastases of ccRCC in mice. An integrated ATAC-seq, ChIP-seq, and transcriptome analysis concluded a tumor suppressor model in which loss of SETD2-mediated H3K36me3 activates enhancers to drive oncogenic transcription through dysregulating histone chaperone recruitment, enhancing histone exchange, and expanding chromatin accessibility. Furthermore, we uncovered mechanism-based therapeutic strategies for SETD2-deficient cancer through inhibition of histone chaperones. Overall, SETD2-loss creates a permissive epigenetic landscape for cooperating oncogenic drivers to amplify transcriptional output, providing unique therapeutic opportunities.

2021-11-15 | GSE146537 | GEO

Gene expression analysis of murine renal tubular epithelial cells upon SETD2 knockout [RNAseq_RTE]

2021-11-15 | GSE146541 | GEO