Distinct functions of histone H3, lysine 4 methyltransferases in normal and malignant hematopoiesis

Yang, Weiwei; Ernst, Patricia

doi:10.1097/moh.0000000000000346

Cited by 37 publications

(33 citation statements)

References 63 publications

(78 reference statements)

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“…Loss of Dpy30 results in the accumulation of hematopoietic stem and progenitor cells, while peripheral cells are depleted. This is consistent with the analysis of Mll1, which indicated that this MTase is required for proper development of the hematopoietic system [ 73 ]. Thus, the components of the WRAD complex, which have been analyzed thus far by knockout studies, are essential for mouse and/or organ development.…”

Section: Kmt2 Complexes Are Essential For Development and Are Affesupporting

confidence: 92%

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Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin

Bochynska

Lüscher-Firzlaff

Lüscher

2018

Cells

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Regulation of gene expression is achieved by sequence-specific transcriptional regulators, which convey the information that is contained in the sequence of DNA into RNA polymerase activity. This is achieved by the recruitment of transcriptional co-factors. One of the consequences of co-factor recruitment is the control of specific properties of nucleosomes, the basic units of chromatin, and their protein components, the core histones. The main principles are to regulate the position and the characteristics of nucleosomes. The latter includes modulating the composition of core histones and their variants that are integrated into nucleosomes, and the post-translational modification of these histones referred to as histone marks. One of these marks is the methylation of lysine 4 of the core histone H3 (H3K4). While mono-methylation of H3K4 (H3K4me1) is located preferentially at active enhancers, tri-methylation (H3K4me3) is a mark found at open and potentially active promoters. Thus, H3K4 methylation is typically associated with gene transcription. The class 2 lysine methyltransferases (KMTs) are the main enzymes that methylate H3K4. KMT2 enzymes function in complexes that contain a necessary core complex composed of WDR5, RBBP5, ASH2L, and DPY30, the so-called WRAD complex. Here we discuss recent findings that try to elucidate the important question of how KMT2 complexes are recruited to specific sites on chromatin. This is embedded into short overviews of the biological functions of KMT2 complexes and the consequences of H3K4 methylation.

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Section: Kmt2 Complexes Are Essential For Development and Are Affesupporting

confidence: 92%

“…The recombinant A/B complexes are predominantly mono- and di-methylating H3K4 with low tri-methylation activity [ 72 ]. In cells, however, these complexes are important for H3K4me3 [ 73 ]. The C/D complexes are preferentially mono-methylating H3K4 [ 74 , 75 , 76 , 77 , 78 , 79 ].…”

Section: Methylation Of Histone H3 At Lysinementioning

confidence: 99%

Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin

Bochynska

Lüscher-Firzlaff

Lüscher

2018

Cells

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“…Concomitant SET1A and SETD1B localization appears as largely nonoverlapping puncta along the euchromatin in the nucleus, suggesting that each protein binds to a unique set of target genes, thereby making nonredundant contributions to the epigenetic control of chromatin structure and gene expression . The mixed lineage leukemia ( MLL ) family of proteins (including MLL1‐MLL4 , SET1A and SETD1B ) specifically methylatesLys4 of histone H3 and plays a pivotal role in the transcriptional regulation of genes involved in hematopoiesis and development . Recent studies have provided evidence that TP53 is the target of SET1/COMPASS and have suggested that these genes may cooperate and function as a tumor suppressor .…”

Section: Discussionmentioning

confidence: 99%

SET domain containing 1B gene is mutated in primary hepatic neuroendocrine tumors

Yang

Huang

Chen

et al. 2019

Intl Journal of Cancer

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Primary hepatic neuroendocrine tumors (PHNETs) are extremely rare NETs originating from the liver. These tumors are associated with heterogeneous prognosis, and few treatment targets for PHNETs have been identified. Because the major genetic alterations in PHNET are still largely unknown, we performed whole-exome sequencing of 22 paired tissues from PHNET patients and identified 22 recurring mutations of somatic genes involved in the following activities: epigenetic modification (BPTF, MECP2 and WDR5), cell cycle (TP53, ATM, MED12, DIDO1 and ATAD5) and neural development (UBR4, MEN1, GLUL and GIGYF2). Here, we show that TP53 and the SET domain containing the 1B gene (SETD1B) are the most frequently mutated genes in this set of samples (3/22 subjects, 13.6%). A biological analysis suggests that one of the three SETD1B mutants, A1054del, promotes cell proliferation, migration and invasion compared to wild-type SETD1B. Our work unveils that SETD1B A1054del mutant is functional in PHNET and implicates genes including TP53 in the disease. Our findings thus characterize the mutational landscapes of PHNET and implicate novel gene mutations linked to PHNET pathogenesis and potential therapeutic targets. What's new?Neuroendocrine tumors often metastasize to the liver but primary hepatic neuroendocrine tumors are extremely rare. Here the authors sequenced tumors from 22 patients in China and provide a first look at the mutational landscape of primary hepatic neuroendocrine tumors. The study points to a possible etiological role of the SET domain containing 1B gene (SETD1B) as it was among the most frequently mutated genes, a role that needs to be further explored.

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“…The common CRs in cancer were found to be enriched mostly in readers and writers for histone modification and chromatin remodelers (19%, 56% and 19%, Supplementary Figure S12 ). Among these CRs, we identified some well-known oncogenes, such as KMT2C, SMARCD1 and SMARCA4 ( 1 , 33 , 38 ). For cancer-specific CRs, we found that these CRs included 36% of the DNA methylation erasers and 35% of the histone modification erasers.…”

Section: Resultsmentioning

confidence: 99%

FACER: comprehensive molecular and functional characterization of epigenetic chromatin regulators

et al. 2018

Nucleic Acids Research

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Epigenetic alterations, a well-recognized cancer hallmark, are driven by chromatin regulators (CRs). However, little is known about the extent of CR deregulation in cancer, and less is known about their common and specialized roles across various cancers. Here, we performed genome-wide analyses and constructed molecular signatures and network profiles of functional CRs in over 10 000 tumors across 33 cancer types. By integration of DNA mutation, genome-wide methylation, transcriptional/post-transcriptional regulation, and protein interaction networks with clinical outcomes, we identified CRs associated with cancer subtypes and clinical prognosis as potential oncogenic drivers. Comparative network analysis revealed principles of CR regulatory specificity and functionality. In addition, we identified common and specific CRs by assessing their prevalence across cancer types. Common CRs tend to be histone modifiers and chromatin remodelers with fundamental roles, whereas specialized CRs are involved in context-dependent functions. Finally, we have made a user-friendly web interface-FACER (Functional Atlas of Chromatin Epigenetic Regulators) available for exploring clinically relevant CRs for the development of CR biomarkers and therapeutic targets. Our integrative analysis reveals specific determinants of CRs across cancer types and presents a resource for investigating disease-associated CRs.

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Distinct functions of histone H3, lysine 4 methyltransferases in normal and malignant hematopoiesis

Cited by 37 publications

References 63 publications

Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin

Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin

SET domain containing 1B gene is mutated in primary hepatic neuroendocrine tumors

FACER: comprehensive molecular and functional characterization of epigenetic chromatin regulators

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