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The effects of H3.3K27M mutation on developing mouse brain and cooperation with Trp53 on enhancing tumorigenesis in the genetic model of H3.3K27M [RNA-Seq]

ABSTRACT: Diffuse intrinsic pontine gliomas (DIPG) are devastating pediatric brain tumors for which there is no effective therapy. A lack of pre-clinical genetic models has affected efforts to develop therapies targeted to DIPG. Over 60% of DIPG patients carry a mutation in the histone H3F3A gene (H3.3K27M) that is often accompanied by a mutation in the TP53 gene. Here we created a genetic model in which H3.3K27M is expressed under the mouse Fabp7 promoter. These mice have disrupted embryonic development and increased susceptibility to development of lymphomas. Crosses to Trp53 knockout mice further accelerated lymphomagenesis and led to brain tumour development. Some but not all tumours acquired additional oncogenic alterations. The brain tumours faithfully recapitulate the expression profiles of DIPG patients, and brain tumours and lymphomas share significant similarities in pathway alterations, pointing to a core H3.3K27M transcriptome. Overall, this mouse model provides key insights into how H3.3K27M mutations regulate DIPG at the cellular and tumour level.

ORGANISM(S): Mus musculus

PROVIDER: GSE120882 | GEO | 2020/10/27

REPOSITORIES: GEO

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The effects of H3.3K27M mutation on developing mouse brain and cooperation with Trp53 on enhancing tumorigenesis in the genetic model of H3.3K27M [Exome-Seq]

Project description:Diffuse intrinsic pontine gliomas (DIPG) are devastating pediatric brain tumors for which there is no effective therapy. A lack of pre-clinical genetic models has affected efforts to develop therapies targeted to DIPG. Over 60% of DIPG patients carry a mutation in the histone H3F3A gene (H3.3K27M) that is often accompanied by a mutation in the TP53 gene. Here we created a genetic model in which H3.3K27M is expressed under the mouse Fabp7 promoter. These mice have disrupted embryonic development and increased susceptibility to development of lymphomas. Crosses to Trp53 knockout mice further accelerated lymphomagenesis and led to brain tumour development. Some but not all tumours acquired additional oncogenic alterations. The brain tumours faithfully recapitulate the expression profiles of DIPG patients, and brain tumours and lymphomas share significant similarities in pathway alterations, pointing to a core H3.3K27M transcriptome. Overall, this mouse model provides key insights into how H3.3K27M mutations regulate DIPG at the cellular and tumour level.

2020-10-27 | GSE120883 | GEO

H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in paediatric high-grade glioma cells

Project description:Diffuse intrinsic pontine gliomas (DIPG) are a deadly paediatric brain tumours, non-resectable due to brainstem localisation and diffusive growth. Patients with DIPG have a dismal prognosis of 9-12 months of survival with no effective therapy. Over 80% of DIPGs harbour a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine to methionine substitution (H3K27M). H3K27M causes global epigenetic alterations (a loss of H3K27 trimethylation and an increase in H3K27 acetylation) resulting in aberrant gene expression. To date, no therapeutic strategy exists to suppress the levels of oncogenic H3K27M. We show that pan-HDAC inhibitors (HDACi) lead to the temporary but significant reduction in the H3.33K27M protein (up to 80%) in multiple glioma cell lines expressing the H3.3K27M histone variant, without changes in the H3F3A mRNA expression. The H3.3K27M occupancy at the chromatin is greatly reduced upon HDACi (SB939) treatment, as shown by ChIPseq analysis. H3.3K27M loss is most striking at SB939-upregulated genes suggesting the role in repression of these genes. In addition, genes previously reported as H3K27M-dependent become downregulated in response to SB939 treatment. We discover that the SB939-mediated loss of H3.3K27M is partially blocked by a lysosomal inhibitor, chloroquine. Moreover, the loss of H3.3K27M is facilitated by co-occurrence of H2A.Z, as evidenced by the knock-down of H2A.Z histone isoforms. ChIPseq analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. Altogether, we provide new insight into disease-specific mechanism of HDAC inhibition and demonstrate pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings open a new possibility to directly target the H3.3K27M oncohistone, which may be exploited in future therapies.

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Project description:Recent studies have identified a Lys 27-to-methionine (K27M) mutation at one allele of H3F3A, one of the two genes encoding histone H3 variant H3.3, in 60% of high-grade pediatric glioma cases. The median survival of this group of patients after diagnosis is ∼1 yr. Here we show that the levels of H3K27 di- and trimethylation (H3K27me2 and H3K27me3) are reduced globally in H3.3K27M patient samples due to the expression of the H3.3K27M mutant allele. Remarkably, we also observed that H3K27me3 and Ezh2 (the catalytic subunit of H3K27 methyltransferase) at chromatin are dramatically increased locally at hundreds of gene loci in H3.3K27M patient cells. Moreover, the gain of H3K27me3 and Ezh2 at gene promoters alters the expression of genes that are associated with various cancer pathways. These results indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis. We performed chromatin-immunoprecipitation of H3K27me3, H3K4me3, and EZH2 in SF7761 and NSC cell lines. And do RNA-seq in SF7761, SF8828 and NSC cell lines. SF7761 and SF8628 cell lines from patients harboring the histone H3.3 K27M mutation were obtained from Hashizume et al. (2012). NSCs (N7800-100) were purchased from Invitrogen and cultured and maintained in NSC medium (A10509-01, StemPro NSC SFM, Invitrogen).

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Project description:Diffuse intrinsic pontine gliomas (DIPG) are paediatric malignant gliomas developing in the brainstem, where resection is unattainable, leaving palliative radiotherapy as the major standard of care. Patients with DIPG have dismal prognosis of 9-12 months of survival and currently there is no effective therapy. Over 80% of DIPGs harbour a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine to methionine substitution (H3K27M). H3K27M causes global epigenetic alterations (a loss of H3K27 trimethylation and an increase H3K27 acetylation) resulting in aberrant gene expression. To date, no therapeutic strategy exists to suppress the levels of oncogenic H3K27M. We show that pan-HDAC inhibitors (HDACi) lead to the temporary but significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines expressing the H3.3K27M histone variant, without changes in the H3F3A mRNA expression. The H3.3K27M occupancy at the chromatin is greatly reduced upon HDACi (SB939) treatment, as shown by ChIPseq analysis. H3.3K27M loss is most striking at SB939-upregulated genes suggesting re-expression of repressed genes. Certain H3K27M-dependent genes become downregulated in response to SB939 treatment. We discover that the SB939-mediated loss of H3.3K27M is partially blocked by a lysosomal inhibitor chloroquine. Moreover, the loss of H3.3K27M is facilitated by co-occurrence of H2A.Z, as evidenced by the knock-down of H2A.Z histone isoforms. ChIPseq analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. Altogether, we provide new insight into disease-specific mechanism of HDAC inhibition and demonstrate pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings open a new possibility to directly target the H3.3K27M oncohistone, which may be exploited in future therapies.

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