Colorectal Carcinomas With CpG Island Methylator Phenotype 1 Frequently Contain Mutations in Chromatin Regulators

Tahara, Tomomitsu; Yamamoto, Eiko; Madireddi, Priyanka; Suzuki, Hiromu; Maruyama, Reo; Chung, Woonbok; Garriga, Judith; Jelı́nek, Jaroslav; Yamano, Hiro O.; Sugai, Tamotsu; Kondo, Yutaka; Toyota, Minoru; Issa, Jean–Pierre J.; Estecio, Marcos R.

doi:10.1053/j.gastro.2013.10.060

Cited by 79 publications

(72 citation statements)

References 30 publications

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“…Interestingly, CHD8 alterations also have been described as somatic events in gastric, colorectal, skin, and glioblastoma multiforme cancers (11)(12)(13)(14). Despite its evident importance, little is known from previous studies about the cellular and molecular consequences of disrupting a single copy of CHD8 and the regulatory connection between this chromatin-remodeling enzyme and the critical pathways associated with either neurodevelopment or cancer.…”

Section: −10mentioning

confidence: 99%

CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors

Sugathan

Biagioli

Golzio

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

311

360

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Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10 −8) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10 −10). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis.he genetic architecture of autism spectrum disorder (ASD) is complex and heterogeneous. A wave of recent discoveries has identified individual genes that contribute to ASD when they suffer heterozygous inactivation by coding mutation, copy number variation, or balanced chromosomal abnormalities (1-7). Many of these genes fit neatly into current biological models of ASD involving altered synaptic structure and glutamatergic neurotransmission, but others have been surprising, with a less ready biological interpretation, including genes involved in chromatin modification, DNA methylation, cell adhesion, and global transcriptional regulation. This diversity of genes predisposing to ASD suggests either that there are many pathways that independently can result in the autism phenotype or that functionally distinct ASD-risk genes can trigger consequences that converge on a limited number of shared pathways of ASD pathogenesis. Because now experimental tools are available to reduce gene expression specifically in human neural progenitor cells (NPCs), which can mimic the impact of functional hemizygosity, we have explored this question by investigating the functional genomic consequences of suppr...

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Section: −10mentioning

confidence: 99%

CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors

Sugathan

Biagioli

Golzio

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

311

360

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“…A single mutation has been reported in RNF20 in colorectal cancer cells (Barber et al 2008). A recent study of CpG island methylator phenotype 1 (CIMP1)-associated colorectal tumours has shown an enrichment of mutations in genes encoding proteins associated with chromatin remodelling, including a low frequency of mutations in RNF20 and RNF40 (Tahara et al 2014). The effect of hypermethylation, or mutations, on RNF20 protein levels was not investigated in these studies; however, the implication is that these events probably lead to less active RNF20 capable of functioning to monoubiquitinate histone H2B.…”

Section: H2bub1 and Associated Machinery In Primary Tumoursmentioning

confidence: 99%

Histone H2B monoubiquitination: roles to play in human malignancy

Cole¹,

Clifton‐Bligh²,

Marsh³

2014

Endocrine-Related Cancer

117

120

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Ubiquitination has traditionally been viewed in the context of polyubiquitination that is essential for marking proteins for degradation via the proteasome. Recent discoveries have shed light on key cellular roles for monoubiquitination, including as a post-translational modification (PTM) of histones such as histone H2B. Monoubiquitination plays a significant role as one of the largest histone PTMs, alongside smaller, better-studied modifications such as methylation, acetylation and phosphorylation. Monoubiquitination of histone H2B at lysine 120 (H2Bub1) has been shown to have key roles in transcription, the DNA damage response and stem cell differentiation. The H2Bub1 enzymatic cascade involves E3 RING finger ubiquitin ligases, with the main E3 generally accepted to be the RNF20-RNF40 complex, and deubiquitinases including ubiquitin-specific protease 7 (USP7), USP22 and USP44. H2Bub1 has been shown to physically disrupt chromatin strands, fostering a more open chromatin structure accessible to transcription factors and DNA repair proteins. It also acts as a recruiting signal, actively attracting proteins with roles in transcription and DNA damage. H2Bub1 also appears to play central roles in histone cross-talk, influencing methylation events on histone H3, including H3K4 and H3K79. Most significantly, global levels of H2Bub1 are low to absent in advanced cancers including breast, colorectal, lung and parathyroid, marking H2Bub1 and the enzymes that regulate it as key molecules of interest as possible new therapeutic targets for the treatment of cancer. This review offers an overview of current knowledge regarding H2Bub1 and highlights links between dysregulation of H2Bub1-associated enzymes, stem cells and malignancy.

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“…49 In this series, CIMP1 (high level CIMP) was classified based on a panel of 7 markers. A classification of CIMP1 required hypermethylation of the MLH1 gene promoter, as well as 4/6 of the remaining markers.…”

Section: Discussionmentioning

confidence: 99%

Isocitrate dehydrogenase 1R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype

et al. 2014

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The CpG Island Methylator Phenotype (CIMP) is fundamental to an important subset of colorectal cancer; however, its cause is unknown. CIMP is associated with microsatellite instability but is also found in BRAF mutant microsatellite stable cancers that are associated with poor prognosis. The isocitrate dehydrogenase 1 (IDH1) gene causes CIMP in glioma due to an activating mutation that produces the 2-hydroxyglutarate oncometabolite. We therefore examined IDH1 alteration as a potential cause of CIMP in colorectal cancer. The IDH1 mutational hotspot was screened in 86 CIMPpositive and 80 CIMP-negative cancers. The entire coding sequence was examined in 81 CIMP-positive colorectal cancers. Forty-seven cancers varying by CIMP-status and IDH1 mutation status were examined using Illumina 450K DNA methylation microarrays. The R132C IDH1 mutation was detected in 4/166 cancers. All IDH1 mutations were in CIMP cancers that were BRAF mutant and microsatellite stable (4/45, 8.9%). Unsupervised hierarchical cluster analysis identified an IDH1 mutation-like methylation signature in approximately half of the CIMP-positive cancers. IDH1 mutation appears to cause CIMP in a small proportion of BRAF mutant, microsatellite stable colorectal cancers. This study provides a precedent that a single gene mutation may cause CIMP in colorectal cancer, and that this will be associated with a specific epigenetic signature and clinicopathological features.

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Colorectal Carcinomas With CpG Island Methylator Phenotype 1 Frequently Contain Mutations in Chromatin Regulators

Cited by 79 publications

References 30 publications

CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors

CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors

Histone H2B monoubiquitination: roles to play in human malignancy

Isocitrate dehydrogenase 1R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype

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