CTCF-Mediated Genome Architecture Regulates the Dosage of Mitotically Stable Mono-allelic Expression of Autosomal Genes

Chandradoss, Keerthivasan Raanin; Chawla, Bindia; Dhuppar, Shivnarayan; Nayak, Rakhee; Ramachandran, Rajesh; Kurukuti, Sreenivasulu; Mazumder, Aprotim; Sandhu, Kuljeet Singh

doi:10.1016/j.celrep.2020.108302

Cited by 4 publications

(6 citation statements)

References 96 publications

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“…Previous in vitro studies of cell lines have suggested the existence of random monoallelic expression (RME) for thousands of autosomal genes in mice and humans due to non-genetic mechanisms (Gimelbrant et al, 2007;Eckersley-Maslin et al, 2014;Gendrel et al, 2014). RME in cell lines is mitotically heritable and has been shown to be regulated by levels of the insulator protein, CTCF, in some cases (Chandradoss et al, 2020). However, the prevalence of widespread autosomal RME that is clonal (mitotically heritable) is currently debated and little is known about the existence of such effects in vivo (Reinius and Sandberg, 2015;Rv et al, 2021;Vigneau et al, 2018).…”

Section: Stochastic Gene Regulatory Effects At the Allele Level As A Potential Driver Of Tumor Cell Diversity And Adaptabilitymentioning

confidence: 99%

Starvation and Climate Change—How to Constrain Cancer Cell Epigenetic Diversity and Adaptability to Enhance Treatment Efficacy

Gregg

2021

Front. Ecol. Evol.

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Advanced metastatic cancer is currently not curable and the major barrier to eliminating the disease in patients is the resistance of subpopulations of tumor cells to drug treatments. These resistant subpopulations can arise stochastically among the billions of tumor cells in a patient or emerge over time during therapy due to adaptive mechanisms and the selective pressures of drug therapies. Epigenetic mechanisms play important roles in tumor cell diversity and adaptability, and are regulated by metabolic pathways. Here, I discuss knowledge from ecology, evolution, infectious disease, species extinction, metabolism and epigenetics to synthesize a roadmap to a clinically feasible approach to help homogenize tumor cells and, in combination with drug treatments, drive their extinction. Specifically, cycles of starvation and hyperthermia could help synchronize tumor cells and constrain epigenetic diversity and adaptability by limiting substrates and impairing the activity of chromatin modifying enzymes. Hyperthermia could also help prevent cancer cells from entering dangerous hibernation-like states. I propose steps to a treatment paradigm to help drive cancer extinction that builds on the successes of fasting, hyperthermia and immunotherapy and is achievable in patients. Finally, I highlight the many unknowns, opportunities for discovery and that stochastic gene and allele level epigenetic mechanisms pose a major barrier to cancer extinction that warrants deeper investigation.

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Section: Stochastic Gene Regulatory Effects At the Allele Level As A Potential Driver Of Tumor Cell Diversity And Adaptabilitymentioning

confidence: 99%

Starvation and Climate Change—How to Constrain Cancer Cell Epigenetic Diversity and Adaptability to Enhance Treatment Efficacy

Gregg

2021

Front. Ecol. Evol.

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“…"insulator sites") have been associated to different functions, including: activation, repression, alternative splicing, and protection from DNA methylation. However, the molecular mechanisms behind these pleiotropic functions remain poorly understood (61). In this scenario of "insulator sites", we also identified a downregulation of Mau2 in the RNA-seq of DIDO3ΔE16 ESC (Table 1).…”

Section: Regulation Of Cohesin Complex Formationmentioning

confidence: 75%

“…This result suggests a role of DIDO3 in chromatin organization as both, CTCF and PRC2 contribute to chromatin long-range interactions (60). Also, CTCF can attract other TFs to chromatin, including tissue-specific transcriptional activators, repressors, cohesin and RNAPII (61,62).…”

Section: Dido3 Binding Sites Contribute To Ctcf-mediated Long-range Chromatin Interactionsmentioning

confidence: 88%

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DIDO3 acts at the interface of RNAPII transcription and chromatin structure regulation

Pons

Serra

Pazos

et al. 2021

Preprint

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Chromatin structure and organization has a key role in gene expression regulation. Here, we integrated ChIP-seq, RNA-seq, Hi-C, epigenetic, and cancer-related mutations data to get insight into the role of Death Inducer Obliterator gene (Dido1) in RNA pol II (RNAPII) transcription and chromatin structure regulation. Analysis of ChIP-seq data of DIDO3, the largest protein isoform of Dido1, revealed binding-sites overlap about 70% with RNAPII and H3K36me3 in the mouse genome, but also significant overlap 10-30% with Polycomb, CTCF, H3K4me3, and H3K27ac. Based on this analysis we propose that DIDO3 PHD domain interacts with H3K36me3 posttranslational modification. Integrating multi-omics data we describe how DIDO3 potentially recruit several transcription factors, including RNAPII, and also regulates genes transcribing those same transcription factors. DIDO3 regulation of the genes traduced into proteins to which it binds puts DIDO3 in the center of intricate feedback loops. We showed, by using data from a DIDO3 mutant, that DIDO3 C-terminus is responsible for most of these transcriptional regulation, and is also implicated in other very important pathways by regulating genes encoding for Polycomb-accessory proteins, subunits of the SWI/SNF chromatin remodelling, or Set1/COMPASS chromatin modifier complexes. These multi-protein complexes control gene activation or silencing and also play a role in tumour development. DIDO3 C-terminus region and splice-site for alternative DIDO2/DIDO3 protein isoforms tended to accumulate recurrent truncating mutations identified in the TCGA Pan-Cancer dataset. We hypothesize that deregulation of DIDO3, as it happens with large epigenetic complexes and long-range interactions, leads to cell differentiation deficiency and cancer development. Overall, we propose here a molecular mechanism by which DIDO3, favour RNAPII pausing and long-range chromatin interactions.

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“…Consistent with the idea of additional mechanisms of MAE maintenance, a SIRT1 activator, BML-278, and a sirtuin inhibitor, salermide, appeared as other primary hits in our screen (see Supplementary Figure S3 ), suggesting that expanded application of the Screen-seq strategy can uncover such additional mechanisms. Additionally, a recent report suggested a role for CTCF-mediated chromatin dynamics in regulating allelic transcriptional states ( Chandradoss et al 2020 ).…”

Section: Discussionmentioning

confidence: 99%

RNA sequencing-based screen for reactivation of silenced alleles of autosomal genes

Gupta

Lafontaine

Vigneau

et al. 2021

G3 Genes|Genomes|Genetics

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In mammalian cells, maternal and paternal alleles usually have similar transcriptional activity. Epigenetic mechanisms such as X-chromosome inactivation (XCI) and imprinting were historically viewed as rare exceptions to this rule. Discovery of autosomal monoallelic expression (MAE) a decade ago revealed an additional allele-specific mode regulating thousands of mammalian genes. Despite MAE prevalence, its mechanistic basis remains unknown. Using an RNA sequencing-based screen for reactivation of silenced alleles, we identified DNA methylation as key mechanism of MAE mitotic maintenance. In contrast with the all-or-nothing allelic choice in XCI, allele-specific expression in MAE loci is tunable, with exact allelic imbalance dependent on the extent of DNA methylation. In a subset of MAE genes, allelic imbalance was insensitive to DNA demethylation, implicating additional mechanisms in MAE maintenance in these loci. Our findings identify a key mechanism of MAE maintenance and provide basis for understanding the biological role of MAE.

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CTCF-Mediated Genome Architecture Regulates the Dosage of Mitotically Stable Mono-allelic Expression of Autosomal Genes

Cited by 4 publications

References 96 publications

Starvation and Climate Change—How to Constrain Cancer Cell Epigenetic Diversity and Adaptability to Enhance Treatment Efficacy

Starvation and Climate Change—How to Constrain Cancer Cell Epigenetic Diversity and Adaptability to Enhance Treatment Efficacy

DIDO3 acts at the interface of RNAPII transcription and chromatin structure regulation

RNA sequencing-based screen for reactivation of silenced alleles of autosomal genes

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