H3K36 methyltransferase NSD1 is essential for normal B1 and B2 cell development and germinal center formation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE208327 | GEO | 2022/11/20
REPOSITORIES: GEO
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Project description:B cells, which consist of two well-defined populations: B1 and B2 cells, which can produce antibodies that are essential for host protection against infections, through virus neutralization, opsonization and antibody-dependent cellular cytotoxicity. Epigenetic modifications, such as DNA methylation and histone modification could regulate immune cell differentiation and functions. In this study, we found a significant reduction of GC response in the B cell specific knockout of H3K36 methyltransferase NSD1 (Mb1-Cre+ NSD1fl/fl, NSD1B KO) mice compared with the wildtype control (Mb1-Cre+ NSD1+/+, NSD1B WT). We also demonstrated reduced production of high-affinity antibody, but increased production of low-affinity antibody in the NSD1B KO mice. Further analysis revealed that loss of NSD1 promoted the development of B1 cells by increasing the expression of Rap1b and Arid3a. In conclusion, our data suggest that NSD1 plays an important role in regulation the development of B1 and B2 cells, and the process of germinal center formation and high-affinity antibody production.
| S-EPMC9750791 | biostudies-literature
Project description:H3K36 methyltransferase NSD1 is essential for normal B1 and B2 cell development and germinal center formation
| PRJNA859190 | ENA
Project description:Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth syndromes, multiple myeloma and lung cancers. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98). Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98-NSD1. We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98-NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus. Experiment Overall Design: Total RNA was extracted from stably transformed progenitors cultured in vitro and the expression levels of mRNA transcripts quantified using the Affymetrix GeneChip Mouse Genome 430 2.0 array, as previously described. The GEO database accession numbers: for progenitors immortalized by HoxA9 (GSM190542, GSM190546, GSM190547); for progenitors immortalized by coexpressed HoxA9 plus Meis1 (GSM190548, GSM190549, GSM190550); for progenitors immortalized by NUP98-NSD1 (GSM190551, GSM190552, GSM190553); and for progenitors immortalized by MLL-ENL (GSM190554). Experiment Overall Design: NOTE: CEL files and dChip data were requested by GEO but not provided.
2008-06-11 | E-GEOD-10071 | biostudies-arrayexpress
Project description:Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth syndromes, multiple myeloma and lung cancers. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98). Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98-NSD1. We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98-NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus. Keywords: expression analysis
2008-01-04 | GSE10071 | GEO
Project description:Methylation of histone 3 lysine 36 (H3K36me) has emerged as an essential epigenetic component for the faithful regulation of gene expression. Despite its demonstrated importance in development, disease, and cancer, the molecular agents responsible for the deposition of H3K36me are not yet well understood. Here, we use a mouse mesenchymal stem cell model to comprehensively perturb the components of the H3K36me deposition machinery and infer the activities of the five most prominent players: SETD2, NSD1, NSD2, NSD3, and ASH1L. We find that H3K36me2 is the most abundant of the three methylation states and that it is predominantly deposited at intergenic regions by NSD1, and in part by NSD2. In contrast, H3K36me1/3 are most abundant within exons and have a positive correlation with gene expression. We further demonstrate that while SETD2 is responsible for depositing most H3K36me3, it also deposits a modest amount of H3K36me2 within transcribed genes. Additionally, loss of SETD2 results in an increase of exonic H3K36me1, suggesting that other H3K36 methyltransferases may prime gene bodies with lower methylation states ahead of transcription. Through a reductive approach, we uncover the genome-wide distribution patterns of NSD3- and ASH1L-catalyzed H3K36me2. While NSD1/2 establish broad intergenic H3K36me2 domains, NSD3 deposits broad H3K36me2 peaks centered on active promoter and enhancer regions. Meanwhile, the activity of ASH1L is focused primarily on the promoters of developmentally relevant genes, and our analyses implicate PBX2 as a potential recruitment factor for ASH1L to these regions. Overall, our study provides new insights into the regulation of H3K36me by the H3K36 methyltransferase family and helps to consolidate the wealth of previous observations in the context of a structured analysis.
2023-10-05 | MSV000093049 | MassIVE
Project description:Chondrocyte differentiation is a critical process for endochondral ossification, which is responsible for long bone development and fracture repair. Considerable progress has been made in understanding the transcriptional control of chondrocyte differentiation; however, epigenetic regulation of chondrocyte differentiation remains to be further studied. NSD1 is a H3K36 (histone H3 at lysine 36) methyltransferase. Here, we showed that mice with Nsd1 deficiency in Prx1+ mesenchymal progenitors but not in Col2+ chondrocytes showed impaired skeletal growth and fracture healing accompanied by decreased chondrogenic differentiation. Via combined RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we identified sex determining region Y box 9 (Sox9), the key transcription factor of chondrogenic differentiation, as a functional target gene of NSD1. Mechanistically, NSD1 regulates Sox9 expression by modulating H3K36me1 and H3K36me2 levels in the Sox9 promoter region, constituting a novel epigenetic regulatory mechanism of chondrogenesis. Moreover, we found that NSD1 can directly activate the expression of hypoxia-inducible factor 1α (HIF1α), which plays a vital role in chondrogenic differentiation through its regulation of Sox9 expression. Collectively, the results of our study reveal crucial roles of NSD1 in regulating chondrogenic differentiation, skeletal growth, and fracture repair and expand our understanding of the function of epigenetic regulation in chondrogenesis and skeletal biology.
| S-EPMC8185073 | biostudies-literature
Project description:Methylation of histone 3 lysine 36 (H3K36me) has emerged as an essential epigenetic component for the faithful regulation of gene expression. Despite its importance in development, disease, and cancer, how the molecular agents collectively shape the genome-wide deposition of H3K36me is unclear. Here, we use mouse mesenchymal stem cells to comprehensively perturb the components of the H3K36me deposition machinery and infer the activities of the five most prominent players: SETD2, NSD1, NSD2, NSD3, and ASH1L. We find that H3K36me2 is the most abundant of the three methylation states and that it is predominantly deposited at intergenic regions by NSD1, and in part by NSD2. In contrast, H3K36me1/3 are most abundant within exons and are positively correlated with gene expression. We demonstrate that while SETD2 is responsible for depositing most H3K36me3, it also deposits H3K36me2 within transcribed genes. Additionally, loss of SETD2 results in an increase of exonic H3K36me1, suggesting that other H3K36 methyltransferases may prime gene bodies with lower methylation states ahead of transcription. Through a reductive approach, we uncover the distribution patterns of NSD3- and ASH1L-catalyzed H3K36me2. While NSD1/2 establish broad intergenic H3K36me2 domains, NSD3 deposits H3K36me2 peaks centered on active promoter and enhancer regions. Meanwhile, the activity of ASH1L is restricted to regulatory elements of developmentally relevant genes, and our analyses implicate PBX2 as a potential recruitment factor. Overall, our study provides new insights into the regulation of H3K36me and helps to consolidate the wealth of previous observations in the context of structured analyses.
2024-09-25 | GSE243566 | GEO
Project description:RNA-seq of splenic follicular B2 cells, peritoneal 5C5 B1 cells and peritoneal B2toB1 cells 30 days post transfer
2019-02-15 | GSE124827 | GEO
Project description:Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1+/- specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1+/- specific signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing. Bisulphite converted DNA from 122 samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip array.
2015-12-16 | E-GEOD-74432 | biostudies-arrayexpress
Project description:B2 cells were purified from spleen by CD19 Microbeads. B1 cells were purified from peritoneal cavity lavage by CD19 microbeads, followed by a depletion of CD23+ cells. RNA was prepared and differential gene expression analysis performed.
2014-08-19 | E-MTAB-2850 | biostudies-arrayexpress