CRISPR-based reagents to study the influence of the epigenome on gene expression

Lavender, Paul; Kelly, A. Paul; Hendy, Eleanor; McErlean, Peter

doi:10.1111/cei.13190

Cited by 7 publications

(4 citation statements)

References 70 publications

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“…On the host side, this has resulted in a spectacular array of molecular immune mechanisms that limit the viral cycle by a range of different strategies. Several of these have come to light due to comparative genomic analysis and have subsequently been validated through biochemical studies [ 128 , 129 ]. These include disparate mechanisms such as the modification of cell-surface molecules to prevent attachment of the virus, targeting of viral nucleic acids by restriction and CRISPR/Cas systems, limiting essential metabolites such as NAD + by targeted degradation, apoptotic or self-targeting mechanisms that limit viral replication and spread by targeting the ribosome or inducing cell-suicide [ 130 ].…”

Section: Resultsmentioning

confidence: 99%

Jumbo Phages: A Comparative Genomic Overview of Core Functions and Adaptions for Biological Conflicts

Iyer

Anantharaman

Krishnan

et al. 2021

Viruses

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Jumbo phages have attracted much attention by virtue of their extraordinary genome size and unusual aspects of biology. By performing a comparative genomics analysis of 224 jumbo phages, we suggest an objective inclusion criterion based on genome size distributions and present a synthetic overview of their manifold adaptations across major biological systems. By means of clustering and principal component analysis of the phyletic patterns of conserved genes, all known jumbo phages can be classified into three higher-order groups, which include both myoviral and siphoviral morphologies indicating multiple independent origins from smaller predecessors. Our study uncovers several under-appreciated or unreported aspects of the DNA replication, recombination, transcription and virion maturation systems. Leveraging sensitive sequence analysis methods, we identify novel protein-modifying enzymes that might help hijack the host-machinery. Focusing on host–virus conflicts, we detect strategies used to counter different wings of the bacterial immune system, such as cyclic nucleotide- and NAD+-dependent effector-activation, and prevention of superinfection during pseudolysogeny. We reconstruct the RNA-repair systems of jumbo phages that counter the consequences of RNA-targeting host effectors. These findings also suggest that several jumbo phage proteins provide a snapshot of the systems found in ancient replicons preceding the last universal ancestor of cellular life.

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Section: Resultsmentioning

confidence: 99%

Jumbo Phages: A Comparative Genomic Overview of Core Functions and Adaptions for Biological Conflicts

Iyer

Anantharaman

Krishnan

et al. 2021

Viruses

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“…To clarify the relationship between the epigenome and transcriptome in asthma, we employed a CRISPR-Cas9-based approach to recapitulate the epigenome of asthma BECs in human embryonic kidney (HEK293T) cells in vitro ( Lavender et al, 2018 ). HEKs were chosen because they do not express some of the genes upregulated in asthma ( CLCA1 , POSTN , SERPINB2 ) and as such mirror expression of healthy BECs.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, we found that targeting of DERs within asthma-SEs at SERPINB2 did not result in induction of gene expression ( Supplementary Figure S1I ). Regardless, dCas9-based epigenome editing provides a tremendous tool to help clarify the functional consequences of asthma-associated changes in the epigenome ( Lavender et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Profiling of H3K27Ac Reveals the Influence of Asthma on the Epigenome of the Airway Epithelium

et al. 2020

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BackgroundAsthma is a chronic airway disease driven by complex genetic–environmental interactions. The role of epigenetic modifications in bronchial epithelial cells (BECs) in asthma is poorly understood.MethodsWe piloted genome-wide profiling of the enhancer-associated histone modification H3K27ac in BECs from people with asthma (n = 4) and healthy controls (n = 3).ResultsWe identified n = 4,321 (FDR < 0.05) regions exhibiting differential H3K27ac enrichment between asthma and health, clustering at genes associated predominately with epithelial processes (EMT). We identified initial evidence of asthma-associated Super-Enhancers encompassing genes encoding transcription factors (TP63) and enzymes regulating lipid metabolism (PTGS1). We integrated published datasets to identify epithelium-specific transcription factors associated with H3K27ac in asthma (TP73) and identify initial relationships between asthma-associated changes in H3K27ac and transcriptional profiles. Finally, we investigated the potential of CRISPR-based approaches to functionally evaluate H3K27ac-asthma landscape in vitro by identifying guide-RNAs capable of targeting acetylation to asthma DERs and inducing gene expression (TLR3).ConclusionOur small pilot study validates genome-wide approaches for deciphering epigenetic mechanisms underlying asthma pathogenesis in the airways.

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“…Inactivation of Cas9 → dCas9 leads to a protein that no longer has nuclease activity but a stable DNA binding domain, that can be targeted using sgRNAs. There are various options for epieffector domains, including VPR/VP64 transactivation domains, the DNA demethylating TET domain or DNMT3A domain [ 195 , 196 , 198 , 199 ].…”

Section: Epigenetic Mechanisms As Drug Targetsmentioning

confidence: 99%

The Relevance of Gender in Tumor-Influencing Epigenetic Traits

et al. 2019

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Tumorigenesis as well as the molecular orchestration of cancer progression are very complex mechanisms that comprise numerous elements of influence and regulation. Today, many of the major concepts are well described and a basic understanding of a tumor's fine-tuning is given. Throughout the last decade epigenetics has been featured in cancer research and it is now clear that the underlying mechanisms, especially DNA and histone modifications, are important regulators of carcinogenesis and tumor progression. Another key regulator, which is well known but has been neglected in scientific approaches as well as molecular diagnostics and, consequently, treatment conceptualization for a long time, is the subtle influence patient gender has on molecular processes. Naturally, this is greatly based on hormonal differences, but from an epigenetic point of view, the diverse susceptibility to stress and environmental influences is of prime interest. In this review we present the current view on which and how epigenetic modifications, emphasizing DNA methylation, regulate various tumor diseases. It is our aim to elucidate gender and epigenetics and their interconnectedness, which will contribute to understanding of the prospect molecular orchestration of cancer in individual tumors.

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CRISPR-based reagents to study the influence of the epigenome on gene expression

Cited by 7 publications

References 70 publications

Jumbo Phages: A Comparative Genomic Overview of Core Functions and Adaptions for Biological Conflicts

Jumbo Phages: A Comparative Genomic Overview of Core Functions and Adaptions for Biological Conflicts

Profiling of H3K27Ac Reveals the Influence of Asthma on the Epigenome of the Airway Epithelium

The Relevance of Gender in Tumor-Influencing Epigenetic Traits

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