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Ependymomas exist within distinct genetic subgroups, but the molecular diversity within individual ependymomas is unknown. We perform multiplatform molecular profiling of 6 spatially distinct samples from an ependymoma with C11orf95-RELA fusion. DNA methylation and RNA sequencing distinguish clusters of samples according to neuronal development gene expression programs that could also be delineated by differences in magnetic resonance blood perfusion. Exome sequencing and phylogenetic analysis reveal epigenomic intratumor heterogeneity and suggest that chromosomal structural alterations may precede accumulation of single-nucleotide variants during ependymoma tumorigenesis. In sum, these findings shed light on the oncogenesis and intratumor heterogeneity of ependymoma.

Pancreas development is tightly controlled by multilayer mechanisms. Despite years of effort, large gaps remain in understanding how histone modifications coordinate pancreas development. SETD2, a predominant histone methyltransferase of H3K36me3, plays a key role in embryonic stem cell differentiation, whose role in organogenesis remains elusive. Here, by combination of cleavage under targets and tagmentation (CUT&Tag), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and bulk RNA sequencing, we show a dramatic increase in the H3K36me3 level from the secondary transition phase and decipher the related transcriptional alteration. Using single-cell RNA sequencing, we define that pancreatic deletion of Setd2 results in abnormalities in both exocrine and endocrine lineages: hyperproliferative tip progenitor cells lead to abnormal differentiation; Ngn3+ endocrine progenitors decline due to the downregulation of Nkx2.2 , leading to insufficient endocrine development. Thus, these data identify SETD2 as a crucial player in embryonic pancreas development, providing a clue to understanding the dysregulation of histone modifications in pancreatic disorders. [Display omitted] • H3K36me3 signals emerge from the second transition stage of embryonic pancreas development • Pancreatic deletion of Setd2 leads to abnormalities in exocrine and endocrine lineages • Setd2 loss propels tip progenitors from quiescence to proliferation • Setd2-H3K36me3 regulates Ngn3+ endocrine progenitors via Nkx2.2 Lu et al. report the role of Setd2-H3K36me3 axis in regulating murine pancreatic organogenesis at both histological and single-cell levels and further explain the molecular mechanism through the multi-omics analysis of RNA-seq, ATAC-seq, and CUT&Tag assays. [ABSTRACT FROM AUTHOR]

Tumors with mutations in chromatin regulators present attractive targets for DNA hypomethylating agent 5-aza-2′-deoxycytidine (DAC) therapy, which further disrupts cancer cells' epigenomic fidelity and reactivates transposable element (TE) expression to drive viral mimicry responses. SETD2 encodes a histone methyltransferase (H3K36me3) and is prevalently mutated in advanced kidney cancers. Here, we show that SETD2 -mutant kidney cancer cells are especially sensitive in vitro and in vivo to DAC treatment. We find that the viral mimicry response are direct consequences of mis-splicing events, such as exon inclusions or extensions, triggered by DAC treatment in an SETD2-loss context. Comprehensive epigenomic analysis reveals H3K9me3 deposition, rather than DNA methylation dynamics, across intronic TEs might contribute to elevated mis-splicing rates. Through epigenomic and transcriptomic analyses, we show that SETD2- deficient kidney cancers are prone to mis-splicing, which can be therapeutically exacerbated with DAC treatment to increase viral mimicry activation and provide synergy with combinatorial immunotherapy approaches. [Display omitted] • SETD2-deficient RCC show suppressed RIG-I pathway and TE expression • RCC with SETD2 loss are sensitive to DNMTi treatment • DNMTi treatment induces RNA mis-splicing to increase TE expression • DNMTi and immunotherapy provide synergy in in vivo SETD2-deficient RCC model DNMTi triggers RNA mis-splicing to strengthen viral mimicry in SETD2-deficient kidney cancer cells. Li et al. report that the enhanced sensitivity to DNMTi in SETD2-deficient kidney cancer cells is associated with increased RNA mis-splicing, which up-regulates immune response and provides synergistic anti-tumor effect with combinatorial immunotherapy approaches. [ABSTRACT FROM AUTHOR]

Subsets of group 3 innate lymphoid cells (ILC3s) are heterogeneous in development and function and play differential roles in intestinal immunity. Histone modifications are involved in the fate commitment of immune cells, including ILC3s. Here, we report that deletion of Setd2, histone H3K36 methyltransferase, in ILC3s results in increased generation of NKp46+ILC3s with enhanced cytotoxic signatures and tumor-suppressive capacity. Meanwhile, Rag1 –/– Rorc Cre Setd2 flox/flox mice have fewer CCR6+ILC3s and less defective solitary intestinal lymphoid tissue formation, accompanied by reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) production by NKp46–ILC3s and decreased CD11b+CD103+ dendritic cell accumulation. The deficiency of Setd2 –/– NKp46–ILC3s may contribute to disturbed RORγt+Treg homeostasis and intestinal inflammation in Rag1 –/– Rorc Cre Setd2 flox/flox mice upon T cell reconstitution. Setd2 regulates genome accessibility imprinting gene mRNA expression, with a more profound effect on NKp46+ILC3s than NKp46–ILC3s. Therefore, Setd2 determines distinct chromatin status and transcriptomic programs of ILC3 subsets to affect their function and intestinal immunity. [Display omitted] • Setd2 deficiency leads to increased NKp46+ILC3 generation with anti-tumor capacity • Setd2 supports maintenance of CCR6+ILC3s and SILT formation • Setd2 expression in ILC3s facilitates RORγt+Treg homeostasis • Setd2 imprints gene expression in ILC3s through modulating genome accessibility Chang et al. report the regulation of ILC3s, a subset of the innate lymphoid cells, by histone methyltransferase Setd2. Loss of Setd2 increases the generation and anti-tumor function of NKp46+ILC3s. Setd2 expression in ILC3s also supports homeostasis of the immunosuppressive RORγt+ regulatory T cells and prevents intestinal inflammation. [ABSTRACT FROM AUTHOR]

In addition to oncogene inhibition, targeting tumor suppressor deficiency could provide potential venues for precision cancer medicine. However, the full spectrum of drug vulnerability conferred by tumor suppressor loss remains unclear. We systematically analyzed how loss of 59 common tumor suppressors each affected cellular sensitivity to 26 different types of anticancer therapeutics. The experiments were performed in a one-gene, one-drug manner, and through such a large gene-drug iteration study, we were able to generate a drug sensitivity map that describes numerous examples of drug resistance or hypersensitivity conferred by tumor suppressor loss. We further delineated the mechanisms of several gene-drug interactions, showing that loss of tumor suppressors could modify drug sensitivity at various steps of drug action. This systematic drug sensitivity map highlights potential drug vulnerabilities associated with tumor suppressor loss, which may help expand precision cancer medicine on the basis of tumor suppressor status., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)