Similar Datasets
Project description:H3K36me3 catalyzed by histone methyltransferase SETD2 is one of the most conserved epigenetic marks from yeast to mammals. SETD2 is frequently mutated in multiple cancers and acts as a tumor suppressor. Here, utilizing a liver-specific deletion of Setd2 mice model, we found that Setd2 depletion is sufficient to trigger hepatocarcinoma (HCC) spontaneously. Meanwhile, in a DEN-induced HCC model, Setd2 depletion significantly promoted tumor number and size. The mechanistic study showed that Setd2 suppresses HCC not only through modulating DNA damage response, but also regulating lipid metabolism in liver. Setd2 deficiency down-regulated the expression of cholesterol efflux genes and caused lipid accumulation. ChIP-Seq analysis further revealed that Setd2 deletion induced AP-1 activation in liver, which was probably trigged by accumulated cholesterol. AP-1 is a well-known oncogene in HCC and inhibits p53 in Setd2-deficient cells. Taken together, we found the role of an important epigenetic gene in regulating cholesterol homeostasis and HCC, and revealed the underlying mechanisms.
2021-09-01 | GSE136743 | GEO
Project description:H3K36me3 catalyzed by histone methyltransferase SETD2 is one of the most conserved epigenetic marks from yeast to mammals. SETD2 is frequently mutated in multiple cancers and acts as a tumor suppressor. Here, utilizing a liver-specific deletion of Setd2 mice model, we found that Setd2 depletion is sufficient to trigger hepatocarcinoma (HCC) spontaneously. Meanwhile, in a DEN-induced HCC model, Setd2 depletion significantly promoted tumor number and size. The mechanistic study showed that Setd2 suppresses HCC not only through modulating DNA damage response, but also regulating lipid metabolism in liver. Setd2 deficiency down-regulated the expression of cholesterol efflux genes and caused lipid accumulation. ChIP-Seq analysis further revealed that Setd2 deletion induced AP-1 activation in liver, which was probably trigged by accumulated cholesterol. AP-1 is a well-known oncogene in HCC and inhibits p53 in Setd2-deficient cells. Taken together, we found the role of an important epigenetic gene in regulating cholesterol homeostasis and HCC, and revealed the underlying mechanisms.
2021-09-01 | GSE136742 | GEO
Project description:Deficiency of histone methyltransferase SETD2 in liver leads to abnormal lipid metabolism and hepatocarcinoma
| PRJNA563558 | ENA
Project description:Deficiency of histone methyltransferase SETD2 in liver leads to abnormal lipid metabolism and hepatocarcinoma [RNA-Seq]
| PRJNA563560 | ENA
Project description:Deficiency of histone methyltransferase SETD2 in liver leads to abnormal lipid metabolism and hepatocarcinoma [ChIP-Seq]
| PRJNA563561 | ENA
Project description:Cell size varies between cell types but is tightly regulated by cell intrinsic and extrinsic mechanisms. Cell size control is important for cell function, and changes in cell size are frequently observed in cancer. Here, we uncover a role for SETD2 in regulating cell size. SETD2 is a lysine methyltransferase and a tumor suppressor protein involved in transcription, RNA processing and DNA repair. At the molecular level, SETD2 is best known for associating with RNA polymerase II through its Set2-Rbp1 interacting (SRI) domain and methylating histone H3 on lysine 36 (H3K36) during transcription. Using multiple independent perturbation strategies, we identify SETD2 as a negative regulator of global protein synthesis rates and cell size. We provide evidence that overexpression of the H3K36 demethylase KDM4A or the oncohistone H3.3K36M also increase cell size. In addition, ectopic overexpression of a decoy SRI domain increased cell size, suggesting that the relevant substrate is engaged by SETD2 via its SRI domain. These data add a central role of SETD2 in regulating cellular physiology and warrant further studies on separating the different functions of SETD2 in cancer development.
| S-EPMC9659392 | biostudies-literature
Project description:The histone H3K36 methyltransferase SETD2 is frequently mutated or deleted in a variety of human tumors. Nevertheless, the role of SETD2 loss in oncogenesis remains largely undefined. Here, we found that SETD2 counteracts Wnt signaling and its inactivation promotes intestinal tumorigenesis in mouse models of colorectal cancer (CRC). SETD2 was not required for intestinal homeostasis under steady state; however, upon irradiation, genetic inactivation of Setd2 in mouse intestinal epithelium facilitated the self-renewal of intestinal stem/progenitor cells as well as tissue regeneration. Furthermore, depletion of SETD2 enhanced the susceptibility to tumorigenesis in the context of dysregulated Wnt signaling. Mechanistic characterizations indicated that SETD2 downregulation affects the alternative splicing of a subset of genes implicated in tumorigenesis. Importantly, we uncovered that SETD2 ablation reduces intron retention of dishevelled segment polarity protein 2 (DVL2) pre-mRNA, which would otherwise be degraded by nonsense-mediated decay, thereby augmenting Wnt signaling. The signaling cascades mediated by SETD2 were further substantiated by a CRC patient cohort analysis. Together, our studies highlight SETD2 as an integral regulator of Wnt signaling through epigenetic regulation of RNA processing during tissue regeneration and tumorigenesis.
| S-EPMC5669571 | biostudies-literature
Project description:Histone H3 of nucleosomes positioned on active genes is trimethylated at Lys36 (H3K36me3) by the SETD2 (also termed KMT3A/SET2 or HYPB) methyltransferase. Previous studies in yeast indicated that H3K36me3 prevents spurious intragenic transcription initiation through recruitment of a histone deacetylase complex, a mechanism that is not conserved in mammals. Here, we report that downregulation of SETD2 in human cells leads to intragenic transcription initiation in at least 11% of active genes. Reduction of SETD2 prevents normal loading of the FACT (FAcilitates Chromatin Transcription) complex subunits SPT16 and SSRP1, and decreases nucleosome occupancy in active genes. Moreover, co-immunoprecipitation experiments suggest that SPT16 is recruited to active chromatin templates, which contain H3K36me3-modified nucleosomes. Our results further show that within minutes after transcriptional activation, there is a SETD2-dependent reduction in gene body occupancy of histone H2B, but not of histone H3, suggesting that SETD2 coordinates FACT-mediated exchange of histone H2B during transcription-coupled nucleosome displacement. After inhibition of transcription, we observe a SETD2-dependent recruitment of FACT and increased histone H2B occupancy. These data suggest that SETD2 activity modulates FACT recruitment and nucleosome dynamics, thereby repressing cryptic transcription initiation.
| S-EPMC3597667 | biostudies-literature
Project description:Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next-generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2 deletions or mutations were often observed as a clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy had reduced progression-free and overall survival compared with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease.
| S-EPMC5023049 | biostudies-literature
Project description:The diverse repertoire of T cell receptors (TCR) and immunoglobulins is generated through the somatic rearrangement of respective V, D and J gene segments, termed V(D)J recombination, during early T or B cell development. However, epigenetic regulation of V(D)J recombination is still not fully understood. Here we show that the deficiency of Setd2, a histone methyltransferase that catalyzes lysine 36 trimethylation on histone 3 (H3K36me3) in mice, causes a severe developmental block of thymocytes at the CD4-CD8- DN3 stage. While H3K36me3 is normally enriched at the TCRβ locus, Setd2 deficiency reduces TCRβ H3K36me3 and suppresses TCRβ V(D)J rearrangement by impairing RAG1 binding to TCRβ loci and the DNA double-strand break repair. Similarly, Setd2 ablation also impairs immunoglobulin V(D)J rearrangement to induce B cell development block at the pro-B stage. Lastly, SETD2 is frequently mutated in patients with primary immunodeficiency. Our study thus demonstrates that Setd2 is required for optimal V(D)J recombination and normal lymphocyte development.
| S-EPMC6659703 | biostudies-literature