Histone Variant and Cell Context Determine H3K27M Reprogramming of the Enhancer Landscape and Oncogenic State

Nagaraja, Surya; Quezada, Michael A.; Gillespie, Shawn; Arzt, Marlene; Lennon, James; Woo, Pamelyn; Hovestadt, Volker; Kambhampati, Madhuri; Filbin, Mariella G.; Suvà, Mario L.; Nazarian, Javad; Monje, Michelle

doi:10.1016/j.molcel.2019.08.030

Cited by 144 publications

(172 citation statements)

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“…Isogenic models examining H3K27M-mediated H3K27ac changes have shown that the majority of this deposition is restricted to cell state and lineage genes rather than affecting de novo genomic elements (44). To begin examining the role that H3K27 modifications might play in normal AFF4 regulation, we first analyzed reference chromatin-immunoprecipitation sequencing (ChIP-seq) datasets from neuroepithelial stem cells (ENCODE Project ENCSR978RSW), hPSC-derived oligodendrocyte precursor cells (iOPCs) (45), and surgical samplings of mature brain from various anatomical regions (ENCODE Project ENCSR107PPJ, ENCSR374BLY, ENCSR528DQE, ENCSR234PGX) (46). In either the neuroepithelial stem cell or iOPC state, the AFF4 promoter bears an activating signature with broad H3K27ac deposition.…”

Section: The H3k27m Mutation Perturbs Epigenetic Regulation Of Aff4mentioning

confidence: 99%

Super elongation complex as a targetable dependency in diffuse midline glioma

Dahl

Danis

Balakrishnan

et al. 2020

Preprint

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AbstractMutations in the histone 3 gene (H3K27M) are the eponymous drivers in diffuse intrinsic pontine gliomas (DIPGs) and other diffuse midline gliomas (DMGs), aggressive pediatric brain cancers for which no curative therapy currently exists. The salient molecular consequence of these recurrent oncohistones is a global loss of repressive H3K27me3 residues and broad epigenetic dysregulation. In order to identify specific, therapeutically targetable epigenetic dependencies within this disease context, we performed an shRNA screen targeting 408 genes classified as epigenetic/chromatin-associated molecules in patient-derived DMG cultures. This approach identified AFF4, the scaffold protein of the super elongation complex (SEC), as a previously-undescribed dependency in DMG. Interrogation of SEC function demonstrated a key role for maintaining DMG cell viability and clonogenic potential while promoting self-renewal of DMG tumor stem cells. Small-molecule inhibition of the SEC with the highly-specific, clinically relevant CDK9 inhibitors atuveciclib and AZD4573 restores regulatory RNA polymerase II pausing, promotes cellular differentiation, and leads to potent anti-tumor effect both in vitro and in patient-derived xenograft models. These studies present a biologic rationale for translational exploration of CDK9 inhibition as a promising therapeutic approach in a disease which currently has no effective medical therapies.

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Section: The H3k27m Mutation Perturbs Epigenetic Regulation Of Aff4mentioning

confidence: 99%

Super elongation complex as a targetable dependency in diffuse midline glioma

Dahl

Danis

Balakrishnan

et al. 2020

Preprint

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“…Live cell imaging has shown that while H3K27M lengthens the time EZH2 spends searching for a target and its residence time once it finds it, the fraction of EZH2 bound to chromatin is unchanged . Other experimental observations using ChIP‐seq have shown that histones bearing the H3.3K27M mutation co‐occur with H3K27ac, PolII and bromodomain proteins, such as BRD2 and BRD4 much more frequently than with H3K27me3 and PRC2 components SUZ12 and EZH2 and quantitative MudPIT mass spectroscopy of immunoprecipitated H3.3K27M mononucleosomes did not show enrichment for PRC2 components . Interestingly, reports of the localization of H3.1K27M have been inconsistent, with one study reporting that the recruitment pattern mirrors H3.3K27M (and thus H3.3WT) deposition and another showing that H3.1K27M is deposited broadly across the genome, in locations consistent with H3.1WT .…”

Section: H3k27m Exerts a Dominant Negative Effect On H3k27me3 Throughmentioning

confidence: 99%

“…Direct comparisons between H3.1K27M and H3.3K27M tumours have begun to show that the isoform of histone H3 bearing the K27M mutation delivers its own transcriptional and epigenetic signature . H3.1K27M could be discriminated from H3.3K27M tumours based on both DNA methylation profile and pattern of H3K27me3 deposition, as well as by gene expression profile, with H3.1K27M tumours having a more mesenchymal and astroglial signature, while H3.3K27M were more proneural and oligodendrocytic .…”

Section: Histone Environment Of H3k27m Mutation Impacts Both Epigenetmentioning

confidence: 99%

“…H3.1K27M could be discriminated from H3.3K27M tumours based on both DNA methylation profile and pattern of H3K27me3 deposition, as well as by gene expression profile, with H3.1K27M tumours having a more mesenchymal and astroglial signature, while H3.3K27M were more proneural and oligodendrocytic . A recent study using conditional expression of H3.1K27M or H3.3K27M in isogenic early OPCs (eOPCs) differentiated from human iPSCs found that within one cell division following induction, the pattern of deposition between H3.1K27M and H3.3K27M was different, while the total loss of H3K27me3 was the same . In H3.3K27M, but not H3.1K27M, loss of H3K27me3 at CpG islands correlated with strength of H3.3 signal, suggesting that direct chromosomal recruitment of PRC2 by K27M mutant histone H3 helps set up these pattern differences.…”

Section: Histone Environment Of H3k27m Mutation Impacts Both Epigenetmentioning

confidence: 99%

“…PRC2‐mediated repression has been shown to be critical to maintaining stemness and preventing differentiation in embryonic stem (ES) cells and H3K27M‐dependent loss of H3K27me3 may act on the cell of origin to repress differentiation and/or reset it to an earlier stem‐like state. Evidence from most experimental studies shows an H3K27M‐dependent increase in expression of stemness genes in neural precursor (NPC) or gliomas, while the bulk of DIPG tumour cells show expression signatures similar to oligodendrocyte precursor (OPC) cells .…”

Section: Introductionmentioning

confidence: 99%

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Invited Review: Emerging functions of histone H3 mutations in paediatric diffuse high‐grade gliomas

Kasper

Baker

2020

Neuropathology Appl Neurobio

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2020) Neuropathology and Applied Neurobiology 46, 73-85 Emerging functions of histone H3 mutations in paediatric diffuse high-grade gliomas Paediatric diffuse high-grade gliomas (pHGG) are rare, but deadly tumours. The discovery of recurrent mutations in the tail of histone H3, changing lysine 27 to methionine, or glycine 34 to arginine or valine, has illuminated a critical role for epigenetic dysregulation in the aetiology of childhood gliomas and opened new avenues of exploration that have resulted in numerous advances for the field. In this review, we describe the current models of H3K27M mutant cancer that are available to the research community and the insights they have provided on tumour biology and the epigenetic and transcriptional effects of histone mutations. We also review the current understanding of the H3G34R/V mutation and the therapeutic outlook for the treatment of pHGG.

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Neuron–Glial Interactions in Health and Brain Cancer

Pan

Monje

2022

Advanced Biology

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Brain tumors are devastating diseases of the central nervous system. Brain tumor pathogenesis depends on both tumor‐intrinsic oncogenic programs and extrinsic microenvironmental factors, including neurons and glial cells. Glial cells (oligodendrocytes, astrocytes, and microglia) make up half of the cells in the brain, and interact with neurons to modulate neurodevelopment and plasticity. Many brain tumor cells exhibit transcriptomic profiles similar to macroglial cells (oligodendrocytes and astrocytes) and their progenitors, making them likely to subvert existing neuron–glial interactions to support tumor pathogenesis. For example, oligodendrocyte precursor cells, a putative glioma cell of origin, can form bona fide synapses with neurons. Such synapses are recently identified in gliomas and drive glioma pathophysiology, underscoring how brain tumor cells can take advantage of neuron–glial interactions to support cancer progression. In this review, it is briefly summarized how neurons and their activity normally interact with glial cells and glial progenitors, and it is discussed how brain tumor cells utilize neuron–glial interactions to support tumor initiation and progression. Unresolved questions on these topics and potential avenues to therapeutically target neuron–glia–cancer interactions in the brain are also pointed out.

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Histone Variant and Cell Context Determine H3K27M Reprogramming of the Enhancer Landscape and Oncogenic State

Cited by 144 publications

References 83 publications

Super elongation complex as a targetable dependency in diffuse midline glioma

Super elongation complex as a targetable dependency in diffuse midline glioma

Invited Review: Emerging functions of histone H3 mutations in paediatric diffuse high‐grade gliomas

Neuron–Glial Interactions in Health and Brain Cancer

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