Similar Datasets
Project description:Methylation of histone H3 lysine-79 is an epigenetic mark for gene regulation in development, cellular differentiation and disease progression. However, it remains poorly understood how this histone mark is translated into downstream effects due to the lack of knowledge of H3K79 methylation ‘readers’. Here, we develop a nucleosome-based photoaffinity probe to capture proteins that recognize H3K79 dimethylation (H3K79me2) in nucleosomal context. In combination with a quantitative proteomics approach, this probe identifies menin as a bona fide “reader” for H3K79me2. Menin directly and selectively binds to the nucleosome with H3K79me2 mark in vitro. In cells, menin is tightly associated with this histone mark on chromatin, particularly in gene bodies. Reading H3K79me2 at intragenic enhancers, menin promotes gene transcription, likely by mediating enhancer–promoter interactions.
2023-02-17 | GSE202592 | GEO
Project description:Methylation of histone H3 lysine-79 is an epigenetic mark for gene regulation in development, cellular differentiation and disease progression. However, it remains poorly understood how this histone mark is translated into downstream effects due to the lack of knowledge of H3K79 methylation ‘readers’. Here, we develop a nucleosome-based photoaffinity probe to capture proteins that recognize H3K79 dimethylation (H3K79me2) in nucleosomal context. In combination with a quantitative proteomics approach, this probe identifies menin as a bona fide “reader” for H3K79me2. Menin directly and selectively binds to the nucleosome with H3K79me2 mark in vitro. In cells, menin is tightly associated with this histone mark on chromatin, particularly in gene bodies. Reading H3K79me2 at intragenic enhancers, menin promotes gene transcription, likely by mediating enhancer–promoter interactions.
2023-02-17 | GSE202591 | GEO
Project description:Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is a tumor suppressor that leads to multiple endocrine tumors upon loss of its function. Menin functions as a transcriptional activator by tethering MLL complex to mediate histone H3 K4 methylation. It also functions as a repressor. However, the molecular mechanism of how menin contributes to the opposite outcome in gene expression is largely unknown. Here, we investigated the role of menin in the epigenetic regulation of transcription mediated by histone covalent modification. We show that the global methylation level of histone H3 K9, as well as H3 K4, was decreased in Men1(-/-) MEF cells. Consistently, menin was able to interact with the suppressor of variegation 3-9 homolog family protein, SUV39H1, to mediate H3 K9 methylation. This interaction decreased when patient-derived MEN1 mutation was introduced into the SUV39H1-interaction domain. We show that menin mediated different chromatin changes depending on target genes. Chromatin immunoprecipitation studies showed that menin directly associated with the GBX2 promoter and menin-dependent recruitment of SUV39H1 was essential for chromatin remodeling and transcriptional regulation. These results provide a molecular basis of how menin functions as a transcriptional repressor and suggest that menin-dependent integration of H3 K9 methylation might play an important role in preventing tumors.
| S-EPMC3668625 | biostudies-literature
Project description:Menin is a ‘reader’ of histone H3 lysine 79 methylation
| PRJNA836614 | ENA
Project description:Menin is a ‘reader’ of histone H3 lysine 79 methylation (ChIP-Seq)
| PRJNA836619 | ENA
Project description:Menin is a ‘reader’ of histone H3 lysine 79 methylation (RNA-Seq)
| PRJNA836620 | ENA
Project description:Disrupting the methylation of telomeric silencing 1-like (DOT1L)-mediated histone H3 lysine 79 has been implicated in MLL fusion-mediated leukemogenesis. Recently, DOT1L has become an attractive therapeutic target for MLL-rearranged leukemias. Rigorous studies have been performed, and much progress has been achieved. Moreover, one DOT1L inhibitor, EPZ-5676, has entered clinical trials, but its clinical activity is modest. Here, we review the recent advances and future trends of various therapeutic strategies against DOT1L for MLL-rearranged leukemias, including DOT1L enzymatic activity inhibitors, DOT1L degraders, protein-protein interaction (PPI) inhibitors, and combinatorial interventions. In addition, the limitations, challenges, and prospects of these therapeutic strategies are discussed. In summary, we present a general overview of DOT1L as a target in MLL-rearranged leukemias to provide valuable guidance for DOT1L-associated drug development in the future. Although a variety of DOT1L enzymatic inhibitors have been identified, most of them require further optimization. Recent advances in the development of small molecule degraders, including heterobifunctional degraders and molecular glues, provide valuable insights and references for DOT1L degraders. However, drug R&D strategies and platforms need to be developed and preclinical experiments need to be performed with the purpose of blocking DOT1L-associated PPIs. DOT1L epigenetic-based combination therapy is worth considering and exploring, but the therapy should be based on a thorough understanding of the regulatory mechanism of DOT1L epigenetic modifications.
| S-EPMC8944089 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-03-09 | GSE183298 | GEO
Project description:Chimeric oncoproteins resulting from fusion of MLL to a wide variety of partnering proteins cause biologically distinctive and clinically aggressive acute leukemias. However, the mechanism of MLL-mediated leukemic transformation is not fully understood. Dot1, the only known histone H3 lysine 79 (H3K79) methyltransferase, has been shown to interact with multiple MLL fusion partners including AF9, ENL, AF10, and AF17. In this study, we utilize a conditional Dot1l deletion model to investigate the role of Dot1 in hematopoietic progenitor cell immortalization by MLL fusion proteins. Western blot and mass spectrometry show that Dot1-deficient cells are depleted of the global H3K79 methylation mark. We find that loss of Dot1 activity attenuates cell viability and colony formation potential of cells immortalized by MLL oncoproteins but not by the leukemic oncoprotein E2a-Pbx1. Although this effect is most pronounced for MLL-AF9, we find that Dot1 contributes to the viability of cells immortalized by other MLL oncoproteins that are not known to directly recruit Dot1. Cells immortalized by MLL fusions also show increased apoptosis, suggesting the involvement of Dot1 in survival pathways. In summary, our data point to a pivotal requirement for Dot1 in MLL fusion protein-mediated leukemogenesis and implicate Dot1 as a potential therapeutic target.
| S-EPMC3040779 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2012-03-02 | GSE24826 | GEO