Project description:We found that the incorporation of histone H3 variant H3.3 was impaired and the accumulation of ZMYND11, which specifically binds to H3.3K36me3, was decreased in NSD2 KO MEFs. About H3K36me2, the average gene body profiles of H3K36me2 showed preferential enrichment of H3K36me2 at the promoter and first half of the genic regions. We examined H3K36me2 mark in super enhancer regions using the ROSE super enhancer prediction program and identified of the 519 super enhancer islands of H3K36me2 in WT MEFs the H3K36me2 signals were decreased in NSD2 KO MEFs
Project description:NSD2 (also known as Whsc1, MMSET) play a role in H3K36 methyl transferase. Here we showed that 199 ISGs of the total 393 ISGs after 2h IFN treatment were up regulated in NSD2 KO MEFs, suggesting negatively regulate ISGs induction. IFN pretreatment creates transcriptional memory. In this study we identified 129 ISGs were memory ISGs and 40 ISGs were non-memory ISGs.
Project description:ZMYND11 is a ‘reader’ protein, which specifically recognizes H3.3K36me3 and regulate RNA polymerase II elongation. Our RNA-seq data showed that 93 ISGs were up regulated, 47 ISGs were down regulated and 48 ISGs were not changed in ZMYND11 KO.
Project description:SPOP is known to bind to serine/theronine-rich degrons on substrate proteins. We identified two degron sequences within the PWWP and MYND domain of ZMYND11, a novel SPOP substrate, and investigated whether ZMYND11 may contribute to the transcriptional output of mutant SPOP in VCaP cancer cells. Hence, we performed over-expression of degron-deficient ZMYND11 and degron-deficient ZMYND11 with W294A mutation in VCaP cells. While WT ZMYND11 constructs can be robustly over-expressed at the mRNA level, only the degron-deficient variants yielded a robost increase in ZMYND11 protein expression. Degron mutant-induced transcriptional perturbations partially mimicked SPOP mutant-induced gene expression changes, suggesting that ZMYND11 is sufficient to recapitulate certain features of mutant SPOP.
Project description:NSD2 is a histone methyltransferase that specifically dimethylates histone H3 lysine 36 (H3K36me2), a modification associated with gene activation. Dramatic overexpression of NSD2 in t(4;14) multiple myeloma (MM) and an activating mutation of NSD2 discovered in acute lymphoblastic leukemia (ALL) are significantly associated with altered gene activation, transcription and DNA damage repair. The partner proteins through which NSD2 may influence critical cellular processes remain poorly defined. In this study, we utilized proximity-based labelling (BioID) combined with label-free quantitative mass spectrometry to identify high confidence NSD2 interacting partners in MM cells.
Project description:Inhibiton of NSD2 by shRNA induces K562 differentiation via increasing erythroid specfic lineage factors The human myelogenous leukemic cell line, K562 undergoes erythroid differentiation by exposure to hemin. Here, we uncovered NSD2 as an innate erythroid differentiation-related factor through the genome-wide CRISPR library screening and explored the regulatory role of NSD2 during myeloid leukemia cell differentiation. We found that NSD2 stability was disrupted by poly-ubiquitination in differentiated K562 cells. Proteomic analysis revealed interaction between NSD2 and an E3 ubiquitin ligase, BRCA1 which ubiquitylates NSD K292 residue. Depletion of BRCA1 stabilized NSD2 protein and suppressed K562 cell differentiation. Furthermore, BRCA1 protein level was decreased in bone marrow tumor, while NSD2 level was elevated. Surprisingly, among BRCA1 mutation(s) discovered in lymphoma patients, BRCA1 K1183R prevented its translocation into the nucleus and did not reduce NSD2 protein level in hemin-treated K562 cells and eventually disrupted cell differentiation. Our results indicated that regulation of NSD2 stability by BRCA1-mediated ubiquitination as a potential therapeutic target process in multiple myeloma.
Project description:The goal of this study was to invetigate the mechanisms by which nsd2 regulate germinal center reaction by comparing RNA-seq data between nsd2 wt and ko germinal center B cells
Project description:This SuperSeries is composed of the following subset Series: GSE29146: NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [ChIP] GSE29147: NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [RNAi] GSE29148: NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [TKO] GSE29150: NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [Transduction] Refer to individual Series
Project description:Humoral immunity in mammals relies on the function of two developmentally and functionally distinct B cell subsets - B1 and B2 cells. While B2 cells are responsible for the adaptive response to environmental antigens, B1 cells regulate the production of polyreactive and low affinity antibodies for innate humoral immunity. The molecular mechanism of B cell specification into different subsets is understudied. We identified lysine methyltransferase NSD2 (MMSET/WHSC1) as a critical regulator of B1 cell development. In contrast to its minor impact on B2 cells, deletion of the catalytic domain of NSD2 in primary B cells impairs the generation of B1 lineage. Thus, NSD2, a histone H3 K36 dimethylase, is the first-in-class epigenetic regulator of a B cell lineage in mice.