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Using CRISPR to understand how cancer mutations happen.
Somatic mutations in cancer genomes can be caused by many different mutational processes, each of which produce distinctive patterns termed “mutational signatures”. Although cancer researchers can now recognize a large number of mutational signatures, exactly how these patterns arise remains unknown. Nik-Zainal and colleagues tackled this problem using a CRISPR-Cas9 genome editing screen to knock out components of the DNA mismatch repair machinery and learn their unique mutational patterns. Based on their data, the authors developed MMRDetect, a computational algorithm to classify the different DNA repair deficiencies and predict tumour responsiveness to immunotherapy.
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CRISPR, surrogate licensing, and scientific discovery.
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Germline Genome Editing and the Functions of Consent.
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Brain tumor modeling using the CRISPR/Cas9 system: state of the art and view to the future.
Although brain tumors have been known tremendously over the past decade, there are still many problems to be solved. The etiology of brain tumors is not well understood and the treatment remains modest. There is in great need to develop a suitable brain tumor models that faithfully mirror the etiology of human brain neoplasm and subsequently get more efficient therapeutic approaches for these disorders. In this review, we described the current status of animal models of brain tumors and analyzed their advantages and disadvantages. Additionally, prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), a versatile genome editing technology for investigating the functions of target genes, and its application were also introduced in our present work. We firstly proposed that brain tumor modeling could be well established via CRISPR/Cas9 techniques. And CRISPR/Cas9-mediated brain tumor modeling was likely to be more suitable for figuring out the pathogenesis of brain tumors, as CRISPR/Cas9 platform was a simple and more efficient biological toolbox for implementing mutagenesis of oncogenes or tumor suppressors that were closely linked with brain tumors.
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The Genetic Basis of Reporter Mouse Strains.
Genetically engineered mouse (GEM) models have been revolutionizing the biomedical studies on deciphering the physiological roles of genes in vivo. In addition to deactivating a gene in mice, diverse strategies have been created to monitor gene expressions and molecular dynamics of specific proteins in vivo. Although gene targeting in mouse embryonic stem (ES) cells was essential for the precise engineering of the mouse genome over almost three decades, this process is a time-consuming, expensive, and laborious one. These days, new technologies that directly apply engineered endonucleases, such as zinc-finger nucleases (ZFNs), Transcription Activator-Like Effector (TALE) Nucleases (TALENs), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system, into the mouse zygotes are enabling us to rapidly replace conventional gene targeting in mouse ES cells. In this chapter, we will describe the principles of reporter mouse strains and the recent advances in generating them using engineered endonucleases.
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Identifying critical lysines in mammalian histone H3 with high-throughput CRISPR prime editing.
Histone post-translational modifications are fundamental to genome regulation, yet dissecting the functions of individual histone marks in mammals remains challenging due to the presence of multiple histone gene copies. Here we develop a high-throughput clustered regularly interspaced short palindromic repeats (CRISPR) prime editing platform enabling precise, reversible and combinatorial mutagenesis of canonical and noncanonical histone H3 genes within their native genomic context. Using systematic lysine-to-arginine substitutions benchmarked against synonymous controls, we identify key residues, including H3K4, H3K9, H3K14, H3K18 and H3K79, whose mutation compromises fitness in mouse embryonic stem cells. We further show that H3K56, linked to genome stability in yeast and Drosophila, has a conserved role in mammalian cells. Through analysis of selected double mutants, we uncover functional crosstalk across residues, with combinations such as H3K27R + H3K36R impairing stem cell self-renewal and altering transcription. Altogether, this study establishes a functional map of histone H3 lysines in mammals and provides a broadly applicable platform for systematic dissection of chromatin regulation.
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In vivo LNP-CRISPR Approaches for the Treatment of Hemophilia.
Hemophilia is a genetic disorder that is caused by mutations in coagulation factor VIII (hemophilia A) or IX (hemophilia B) genes resulting in blood clotting disorders. Despite advances in therapies, such as recombinant proteins and products with extended half-lives, the treatment of hemophilia still faces two major limitations: the short duration of therapeutic effect and production of neutralizing antibodies against clotting factors (inhibitor). To overcome these limitations, new hemophilia treatment strategies have been established such as gene therapy, bispecific antibody, and rebalancing therapy. Although these strategies have shown promising results, it is difficult to achieve a permanent therapeutic effect. Advances in the clustered regularly interspaced short palindromic repeat (CRISPR) technology have allowed sustainable treatment by correcting mutated genes. Since genome editing generates irreversible changes in host genome, safety must be ensured by delivering target organs. Therefore, the delivery tool of the CRISPR system is crucial for safe, accurate, and efficient genome editing. Recently, non-viral vector lipid nanoparticles (LNPs) have emerged as safer tools for delivering CRISPR systems than other viral vectors. Several previous hemophilia pre-clinical studies using LNP-CRISPR showed that sufficient and sustainable therapeutic effects, which means that LNP-CRISPR-mediated genome-editing therapy can be a valid option for the treatment of hemophilia. In this paper, we summarize the latest advancements in the successful treatment of hemophilia and the potential of CRISPR-mediated genome-editing therapy using LNPs.
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Correction of a Disease Mutation using CRISPR/Cas9-assisted Genome Editing in Japanese Black Cattle.
Isoleucyl-tRNA synthetase (IARS) syndrome is a recessive disease of Japanese Black cattle caused by a single nucleotide substitution. To repair the mutated IARS gene, we designed clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) to create a double-strand break near the mutation site. CRISPR/Cas9 and donor DNA that contained a synonymous codon for the correct amino acid and an Aequorea coerulescens Green Fluorescent Protein (AcGFP) cassette with a piggyBac transposase recognition site at both ends were introduced into bovine fetal fibroblast (BFF) cells isolated from a homozygous mutant calf. Recombinant cells were enriched on the basis of expression of AcGFP, and two cell lines that contained the repaired allele were subcloned. We generated somatic cell nuclear transfer (SCNT) embryos from the repaired cells and transferred 22 blastocysts to recipient cows. In total, five viable fetuses were retrieved at Days 34 and 36. PiggyBac transposase mRNA was introduced into BFF cells isolated from cloned foetuses and AcGFP-negative cells were used for second round of cloning. We transferred nine SCNT embryos to recipient cows and retrieved two fetuses at Day 34. Fetal genomic DNA analysis showed correct repair of the IARS mutation without any additional DNA footprint.
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Harnessing the Microbiome: CRISPR-Based Gene Editing and Antimicrobial Peptides in Combating Antibiotic Resistance and Cancer.
The growing crisis of antibiotic resistance and the increasing incidence of cancer have prompted the exploration of innovative approaches, such as gene editing and antimicrobial peptides (AMPs). The human microbiome is integral to various aspects of health, disease, and therapeutic development, influencing metabolic pathways, immune function, and pathogen resistance. Recent advances in gene editing technologies, particularly CRISPR (clustered regularly interspaced short palindromic repeats), have opened new avenues for leveraging the microbiome to address complex medical challenges, including combating multidrug-resistant pathogens and cancer. The microbiome plays a crucial role in combating antibiotic resistance by modulating microbial communities, influencing pathogen survival and susceptibility to treatments. This review explores the microbiome's dynamic role in metabolic regulation, its contribution to cancer management, and how AMPs help maintain homeostasis and exhibit emerging anticancer properties, supported by both preclinical findings and clinical evidence. Additionally, CRISPR-based microbiome engineering offers potential to enhance host-microbiome interactions, optimizing therapeutic outcomes. The integration of microbiome metagenomics and proteomics has led to the discovery of novel AMPs with targeted anticancer effects. Innovative strategies, such as engineered probiotics and CRISPR-based microbiome engineering, present exciting prospects for next-generation therapies. Despite these advances, the translation of microbiome-based therapies into clinical settings remains challenging due to ethical, regulatory, and ecological hurdles. This review underscores the transformative potential of microbiome-based interventions, emphasizing the role of personalized medicine in maximizing therapeutic efficacy. Furthermore, we also address critical research gaps, limitations, and future directions, including optimizing AMP stability, delivery, and bioavailability, as well as overcoming the regulatory and ethical challenges in clinical translation.
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Kingdom-wide CRISPR guide design with ALLEGRO.
Designing CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) single guide RNA (sgRNA) libraries targeting entire kingdoms of life will significantly advance genetic research in diverse and underexplored taxa. Current sgRNA design tools are often species-specific and fail to scale to large, phylogenetically diverse datasets, limiting their applicability to comparative genomics, evolutionary studies, and biotechnology. Here, we introduce ALLEGRO, a combinatorial optimization algorithm designed to compose minimal, yet highly effective sgRNA libraries targeting thousands of species at the same time. Leveraging integer linear programming, ALLEGRO identified compact sgRNA sets simultaneously targeting multiple genes of interest for over 2000 species across the fungal kingdom. We experimentally validated sgRNAs designed by ALLEGRO in Kluyveromyces marxianus, Komagataella phaffii, Yarrowia lipolytica, and Saccharomyces cerevisiae, confirming successful genome edits. Additionally, we employed a generalized Cas9-ribonucleoprotein delivery system to apply ALLEGRO's sgRNA libraries to untested fungal genomes, such as Rhodotorula araucariae. Our experimental findings, together with cross-validation, demonstrate that ALLEGRO facilitates efficient CRISPR genome editing, enabling the development of universal sgRNA libraries applicable to entire taxonomic groups.
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