CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism

Piunti, Andrea; Smith, Edwin R.; Morgan, Marc A.; Ugarenko, Michal; Khaltyan, Natalia; Helmin, Kathryn A.; Ryan, Caila; Murray, David C.; Rickels, Ryan; Yilmaz, Bahar D.; Rendleman, Emily J.; Savas, Jeffrey N.; Singer, Benjamin D.; Bulun, Serdar E.; Shilatifard, Ali

doi:10.1126/sciadv.aax2887

Cited by 89 publications

(111 citation statements)

References 54 publications

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“…Additionally, three independent groups have demonstrated that EZHIP mimics the H3K27M "oncohistone" to cause global H3K27me3 reduction. EZHIP bears a methionine residue, similar to the H3 lysine-to-methionine (K27M) mutation, that is critical for mediating global H3K27me3 reduction [6,7,13]. The genomic distribution of H3K27me3 in H3K27M DIPGS and PFAs show remarkable similarities suggesting that these two tumors may be epigenetically related and share similar pathogenic mechanisms [2,7].…”

mentioning

confidence: 99%

Diffuse intrinsic pontine glioma-like tumor with EZHIP expression and molecular features of PFA ependymoma

Pratt

Quezado

Abdullaev

et al. 2020

acta neuropathol commun

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mentioning

confidence: 99%

Diffuse intrinsic pontine glioma-like tumor with EZHIP expression and molecular features of PFA ependymoma

Pratt

Quezado

Abdullaev

et al. 2020

acta neuropathol commun

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“…Modified reduced representation bisulfite sequencing. Genomic DNA was subjected to mRRBS as previously described (46,54,(59)(60)(61)(62). Bisulfite conversion efficiency averaged 99.52% ± 0.052% (SD) as estimated by the measured frequency of unmethylated CpGs in λ-bacteriophage DNA (New England BioLabs, #N3013S) added at a 1:200 mass ratio to each sample.…”

Section: Discussionmentioning

confidence: 99%

“…experiments. For next-generation sequencing experiments, indicated sample sizes were chosen to obtain a minimum of 10 6 unique CpGs per biological replicate as modeled using the DSS statistical procedures (46,54,(59)(60)(61)(62). Computational analysis was performed using Genomics Nodes and Analytics Nodes on Quest, Northwestern University's High-Performance Computing Cluster.…”

Section: Functional Enrichment Analysis Was Performed Using the Greatmentioning

confidence: 99%

Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Helmin¹,

Morales‐Nebreda²,

Acosta³

et al. 2020

Preprint

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Regulatory T (Treg) cells require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Treg cells persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg cell lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator Uhrf1 is essential for maintenance of methyl-DNA marks that stabilize Treg cellular identity by repressing effector T cell transcriptional programs. Constitutive and induced deficiency of Uhrf1 within Foxp3 + cells resulted in global yet non-uniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg cell lineage, spontaneous inflammation, and enhanced tumor immunity. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg cell genome for both lineage establishment and stability of identity and suppressive function.

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“…One example ( Fig. 4l-o) was a system of six proteins, of which DMAP1, MORF4L1, and JAZF1 were histone acetyltransferases 39,40 , SATB1 had been shown to interact with histone acetyltransferases 41 , SRRM1 had been implicated in chromatin remodeling 42 , and FAM120C had no previously assigned function (Fig. 4o).…”

Section: )mentioning

confidence: 99%

Mapping cell structure across scales by fusing protein images and interactions

Qin

Winsnes

Huttlin

et al. 2020

Preprint

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The eukaryotic cell is a multi-scale structure with modular organization across at least four orders of magnitude 1,2 . Two central approaches for mapping this structure -protein fluorescent imaging and protein biophysical association -each generate extensive datasets but of distinct qualities and resolutions that are typically treated separately 3,4 . Here, we integrate immunofluorescent images in the Human Protein Atlas 5 with ongoing affinity purification experiments from the BioPlex resource 6 to create a unified hierarchical map of eukaryotic cell architecture. Integration involves configuring each approach to produce a general measure of protein distance, then calibrating the two measures using machine learning. The evolving map, called the Multi-Scale Integrated Cell (MuSIC 1.0), currently resolves 69 subcellular systems of which approximately half are undocumented. Based on these findings we perform 134 additional affinity purifications, validating close subunit associations for the majority of systems. The map elucidates roles for poorly characterized proteins, such as the appearance of FAM120C in chromatin; identifies new protein assemblies in ribosomal biogenesis, RNA splicing, nuclear speckles, and ion transport; and reveals crosstalk between cytoplasmic and mitochondrial ribosomal proteins. By integration across scales, MuSIC substantially increases the mapping resolution obtained from imaging while giving protein interactions a spatial dimension, paving the way to incorporate many molecular data types in proteome-wide maps of cells.Advances in confocal microscopy and immunofluorescence (IF) imaging have created systematic pipelines for mapping the spatial distribution of proteins and other molecules within single cells 3,7,8 . Based on these techniques, the Human Protein Atlas (HPA) has launched an extensive effort to map protein subcellular locations using a library of specific fluorescent antibodies targeting more than 13,000 human proteins 5,9 . The use of multiple dyes with separate emission spectra enables locations to be determined relative to known landmarks such as the nucleus, cytoskeleton and endoplasmic reticulum, with the result that most human proteins can be assigned relative positions at sub-micron resolution.In parallel, advances in mass spectrometry (MS) have provided a complementary means of mapping protein coordinates through their biophysical associations with other proteins 4,10 . MS is now routinely combined with affinity purification (AP-MS) 11 or proximity-dependent labeling 12-16 to enumerate physical protein-protein interactions in vitro or in vivo. Combining AP-MS with epitope tagging, the BioPlex project has generated a systematic map of physical interactions covering approximately 7,500 epitope-tagged human proteins (BioPlex 2.0) 6 , including approximately 56,000 candidate interactions organized into more than 400 multimeric protein complexes.Given that protein imaging and biophysical association are leading approaches for mapping cell structure, with growing data resou...

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CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism

Cited by 89 publications

References 54 publications

Diffuse intrinsic pontine glioma-like tumor with EZHIP expression and molecular features of PFA ependymoma

Diffuse intrinsic pontine glioma-like tumor with EZHIP expression and molecular features of PFA ependymoma

Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Mapping cell structure across scales by fusing protein images and interactions

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