🎙️ Episode 70: Scalable Screening of Ternary-Code DNA Methylation Dynamics Associated with Human Traits

🧬 In this episode of Base por Base, we delve into a methodological breakthrough reported by Goldberg et al. (2025) in Cell Genomics, where the authors introduce the methylation screening array (MSA) — a next-generation Infinium BeadChip designed for large-scale, high-throughput profiling of DNA cytosine modifications across human populations. By integrating curated trait-associated loci from epigenome-wide association studies with novel cell-type discriminants, the MSA provides a compact yet comprehensive platform to measure ternary-code methylation (5mC, 5hmC, and unmodified cytosine) at base resolution across diverse tissues .

🔍 Highlights of the study:
The authors demonstrate that the MSA enables scalable and quantitative profiling of human epigenomes, overcoming the coverage–cost trade-offs of previous array designs; they construct a base-resolution atlas of matched total modifications (5modC) and 5hmC landscapes across multiple human tissues; they uncover how distinct patterns of 5modC and 5hmC correlate with gene expression to regulate tissue identity; and they reveal underappreciated roles for 5hmC in aging dynamics and the performance of epigenetic clocks .

🧠 Conclusion:
By consolidating extant EWAS discoveries and leveraging advances in whole-genome methylation profiling, the MSA inaugurates a scalable approach for trait-focused methylation screening in large cohorts. This tool promises to dissect cell-type-specific epigenetic mechanisms underlying human traits, improve the annotation of disease-associated loci, and inform genomics-driven strategies for prevention and precision medicine.

📖 Reference:
Goldberg, D. C., Cloud, C., Lee, S. M., Barnes, B., Gruber, S., Kim, E., Pottekat, A., Westphal, M. S., McAuliffe, L., Majounie, E., Kalayil Manian, M., Zhu, Q., Tran, C., Hansen, M., Stojakovic, J., Parker, J. B., Kohli, R. M., Porecha, R., Renke, N., & Zhou, W. (2025). Scalable screening of ternary-code DNA methylation dynamics associated with human traits. Cell Genomics, 5, 100929. https://doi.org/10.1016/j.xgen.2025.100929

📜 License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

🎙️ Episode 69: Synthetic Dosage Lethality of PLK1 — Targetable Vulnerabilities in PLK1-Overexpressing Cancers
🧬 In this episode of Base por Base, we delve into a comprehensive study by Cunningham et al. (2025) in Cell Genomics that harnesses genome-wide synthetic dosage lethality (SDL) screening to uncover novel therapeutic targets in cancers driven by Polo-like kinase 1 (PLK1). By integrating pooled shRNA and CRISPR-Cas9 screens in both in vitro and in vivo patient-derived xenograft models, followed by single-cell Perturb-seq analysis, the authors identify IGF2BP2 as a critical dependency in PLK1-overexpressing tumor cells. Mechanistic investigations reveal that loss of IGF2BP2 not only destabilizes PLK1 mRNA via disrupted m6A-mediated binding but also impairs mitochondrial oxidative phosphorylation, collectively crippling the energy metabolism of malignant cells. Finally, the first small-molecule inhibitors of IGF2BP2 recapitulate these effects, suppressing tumor growth in xenograft and PDX models and offering a dual-mechanism strategy to overcome tumor heterogeneity .

🔍 Highlights of the study:
Synthetic dosage lethality screening pinpoints IGF2BP2 loss as selectively lethal to PLK1-overexpressing cells.
Disruption of IGF2BP2 reduces PLK1 transcript and protein abundance by impairing m6A-dependent mRNA stabilization.
IGF2BP2 deficiency downregulates key oxidative phosphorylation genes, diminishing mitochondrial ATP production.
Pharmacological inhibition of IGF2BP2 mimics genetic knockout, decreasing cellular respiration and inducing apoptosis in PLK1-high models.
Combined genetic and chemical targeting of IGF2BP2 effectively suppresses tumor growth in multiple breast cancer xenograft and PDX systems.

🧠 Conclusion:
This work establishes IGF2BP2 as a synthetic lethal partner of PLK1, offering a two-pronged attack—downregulation of PLK1 and collapse of mitochondrial bioenergetics—to selectively target PLK1-overexpressing cancers. The identification of IGF2BP2 inhibitors lays the groundwork for precision therapies aimed at overcoming intratumoral heterogeneity in PLK1-driven malignancies.

📖 Reference:
Cunningham, C. E., Vizeacoumar, F. S., Zhang, Y., et al. (2025). Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality. Cell Genomics, 5, 100876. https://doi.org/10.1016/j.xgen.2025.100876

📜 License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) license – https://creativecommons.org/licenses/by/4.0/

🎙️ Episode 68: Indels Empower Antiviral Proteins to Achieve Functional Novelty Beyond Missense Mutations
🧬 In this episode of Base by Base, we dive into pioneering work by Tenthorey et al. (2025) in Cell Genomics that uncovers how insertion and deletion mutations—indels—can unlock evolutionary innovations in the antiviral protein TRIM5α. By applying both deep mutational scanning and a novel deep indel scanning approach to the v1 loop of human TRIM5α, the authors reveal that while no single-nucleotide missense change can confer restriction of the simian immunodeficiency virus SIVsab, a single in-frame duplication of phenylalanine at position 339 instantaneously grants potent antiviral activity against SIVsab and other lentiviruses. This discovery highlights indels as a powerful, yet often overlooked, mechanism for traversing otherwise insurmountable fitness landscapes in host–virus evolutionary arms races.
🔍 Study Highlights: In exhaustive screens, human TRIM5α variants bearing every possible missense change failed to inhibit SIVsab, underscoring the limits of point mutations. Deep indel scanning then identified three in-frame duplication variants that gained SIVsab restriction, with the F339dup alone replicating nine independent rhesus-like mutations in one step. This single amino acid duplication not only enabled defense against SIVsab but also broadened activity to HIV-1 and SIVcpz without impairing existing N-tropic murine leukemia virus restriction, demonstrating a net evolutionary gain. Comparative analysis of primate TRIM5α orthologs confirmed that naturally occurring indels—such as a two-residue insertion in rhesus monkeys and a 20-residue duplication in sabaeus monkeys—directly determine species-specific antiviral specificities.
🧠 Conclusion: By revealing that indel mutations can deliver high-risk, high-reward leaps in protein function inaccessible by missense changes alone, this work reshapes our understanding of antiviral adaptation. Indels emerge not as mere byproducts of genetic drift but as strategic evolutionary tools that enable rapid, robust innovation in host defenses.
📖 Reference: Tenthorey, J. L., del Banco, S., Ramzan, I., Klingenberg, H., Liu, C., Emerman, M., & Malik, H. S. (2025). Indels allow antiviral proteins to evolve functional novelty inaccessible by missense mutations. Cell Genomics, 5, 100818. https://doi.org/10.1016/j.xgen.2025.100818
📜 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) license – https://creativecommons.org/licenses/by/4.0/