Base by Base

374: DNA-guided Cas12a reprogrammed to target RNA

Wu X et al., Nature Biotechnology - The authors engineer synthetic PAM-containing DNA guides (crDNA) that bind Cas12a to form a deoxyribonucleoprotein (DNP) complex that recognizes and cleaves complementary RNA. Structural, biochemical and cellular data define a PAM-dependent activation route distinct from canonical RNA-guided systems and demonstrate applications in sensitive diagnostics and intracellular RNA knockdown. Key terms: DNA-guided Cas12a, crDNA, RNA targeting, SLEUTH diagnostic, RNA knockdown. Study Highlights: The team designed single-stranded PAM-bearing crDNA that assembles with Cas12a to form a stable DNP complex and recruit complementary RNA substrates. Cryo-EM and modeling show crDNA occupies the PI/WED/REC groove, preserves PAM engagement and positions an RNA–DNA heteroduplex for RuvC-mediated cleavage. DNA-guided Cas12a selectively binds and cleaves ssRNA, enables robust trans-cleavage across targets and orthologs, and supports an amplification-coupled SLEUTH diagnostic with attomolar sensitivity. In cells, phosphorothioate-stabilized crDNA with Cas12a produced sequence-specific knockdown of reporter and endogenous transcripts with minimal off-target signal. Conclusion: Cas12a can be reprogrammed into a DNA-guided, RNA-targeting effector: PAM-mediated crDNA engagement forms a catalytically competent complex that achieves sequence-specific RNA cleavage, enabling a new architecture for diagnostics and a proof-of-concept for intracellular RNA knockdown while highlighting stability and optimization challenges. Music: Enjoy the music based on this article at the end of the episode. Article title: DNA-guided CRISPR–Cas12a effectors for programmable RNA recognition and cleavage First author: Wu X Journal: Nature Biotechnology DOI: 10.1038/s41587-026-03120-5 Reference: Wu X., Lam W.H., Zhao Z., Feng X., Zhai Y., Hsing I.-M. DNA-guided CRISPR–Cas12a effectors for programmable RNA recognition and cleavage. Nature Biotechnology (2026). doi:10.1038/s41587-026-03120-5 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/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/dna-guided-cas12a-reprogrammed-to-target-rna QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-22. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited transcript sections describing crDNA design and PAM activation, structural data from cryo-EM, RNA targeting and cleavage mechanics, SLEUTH diagnostic workflow and performance, and intracellular RNA knockdown in cells. - transcript topics: DNA-guided Cas12a concept and crDNA design; PAM-dependent activation and DNP formation; Cryo-EM structure and DNA–RNA duplex within Cas12a; Two-step binding kinetics (Kd1 and Kd2); Trans-cleavage activity and RNA targeting kinetics; SLEUTH diagnostic workflow and performance QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 8 - claims flagged for review: 0 - metadata checks passed: 4 - metadata issues found: 0 Metadata Audited: - article_doi - article_title - article_journal - license Factual Items Audited: - DNA-guided Cas12a can target RNA using crDNA with PAM-dependent activation - crDNA occupies PAM-interacting site to form a DNP complex and enables RNA targeting - Cryo-EM shows a 20-bp DNA–RNA heteroduplex in the Cas12a binding channel with PAM engaging the PI domain - RNA cleavage is Mg2+-dependent via the RuvC active site and exhibits trans-cleavage - SLEUTH achieves attomolar sensitivity and 100% concordance with RT–qPCR on a limited SARS-CoV-2 set - PS-modified crDNA enables intracellular RNA knockdown in HEK293T cells with 56% reduction in EGFP fluorescence and 76% reduction in EGFP mRNA, with minimal off-target effects QC result: Pass.

373: Base by Base 373 — A ciliate rewrites UAA and UAG

McGowan J et al., PLOS Genetics - Genome and transcriptome sequencing of an uncultured Oligohymenophorea ciliate (PL0344) reveals a novel nuclear genetic code in which UAA translates as lysine and UAG as glutamic acid, supported by suppressor tRNAs and phylogenomic context. Key terms: genetic code, ciliate, UAA, UAG, suppressor tRNA. Study Highlights: The authors assembled a macronuclear genome from low-input G&T-Seq data for Oligohymenophorea sp. PL0344 and found widespread in-frame UAA and UAG codons. Codetta and PhyloFisher analyses predict UAA→lysine and UAG→glutamic acid, and multiple corresponding suppressor tRNA genes were identified. UGA remains as a stop and is enriched as tandem stops in the 3' UTR, suggesting selection to limit readthrough. Phylogenomic mapping shows numerous independent genetic code changes across ciliates, making this the first reported case where UAA and UAG specify different amino acids. Conclusion: This study documents a previously unknown nuclear genetic code variant in a ciliate where UAA and UAG have distinct sense meanings, expanding known genetic code diversity and highlighting the need to consider noncanonical codes in genome annotation and evolutionary analyses. Music: Enjoy the music based on this article at the end of the episode. Article title: Identification of a non-canonical ciliate nuclear genetic code where UAA and UAG code for different amino acids First author: McGowan J Journal: PLOS Genetics DOI: 10.1371/journal.pgen.1010913 Reference: McGowan J, Kilias ES, Alacid E, Lipscombe J, Jenkins BH, Gharbi K, et al. (2023) Identification of a non-canonical ciliate nuclear genetic code where UAA and UAG code for different amino acids. PLoS Genet 19(10): e1010913. https://doi.org/10.1371/journal.pgen.1010913 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/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/non-canonical-ciliate-code-373 QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-21. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Substantively audited the transcript sections that discuss genetic code reassignments (UAA/UAG), suppressor tRNAs, UGA handling (stop/Sec), tandem stop codons, sequencing approach (G&T-Seq), and phylogenetic context. - transcript topics: Canonical vs noncanonical genetic code in ciliates; UAA and UAG reassignment to Lys and Glu; Suppressor tRNA genes and wobble binding; G&T-Seq single-cell genome/transcriptome methodology; UGA stop codon usage and tandem stop codons; Phylogenomics and independent genetic code changes in ciliates QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 6 - claims flagged for review: 0 - metadata checks passed: 4 - metadata issues found: 0 Metadata Audited: - article_doi - article_title - article_journal - license Factual Items Audited: - UAA codon reassigned to lysine and UAG codon reassigned to glutamic acid in PL0344 - Presence of multiple suppressor tRNA genes corresponding to UAA (Lys) and UAG (Glu) - tRNA-SeC(UCA) identified, suggesting UGA can encode selenocysteine in addition to stop - UGA codons enriched in the 3'-UTR downstream of genes as tandem stops to mitigate readthrough - Genome assembly size around 69.7 Mb with thousands of transcripts and tRNA genes - Wobble-coupling constraint circumvented; UAA and UAG have different meanings in this organism QC result: Pass.

372: Genes, IQ and Socioeconomic Outcomes in Emerging Adults

Kajonius PJ et al., Scientific Reports - This episode examines a twin-study analysis from the German TwinLife panel showing that cognitive ability at age 23 predicts socioeconomic status at age 27, and that much of this longitudinal association is explained by genetic factors rather than shared or unique environments. Key terms: cognitive ability, IQ, socioeconomic status, genetics, twin study. Study Highlights: Using TwinLife panel data, IQ measured at 23 predicted educational and occupational outcomes at 27 with phenotypic correlations typically above .30. Univariate twin models estimated IQ heritability at about 75% and substantial heritability for SES measures. Bivariate Cholesky decompositions found that genetics accounted for 69–98% of the IQ–SES association and that genetic correlations exceeded environmental correlations. These results held across two education and two occupation measures. Conclusion: In this emerging-adult sample, both IQ and SES showed sizable heritability and the longitudinal link from IQ to future SES was largely attributable to shared genetic influences, suggesting that research and policy should account for genetic contributions when interpreting individual socioeconomic trajectories. Music: Enjoy the music based on this article at the end of the episode. Article title: Longitudinal associations between cognitive ability and socioeconomic status are partially genetic in nature First author: Kajonius PJ Journal: Scientific Reports DOI: 10.1038/s41598-026-37786-3 Reference: Kajonius PJ. Longitudinal associations between cognitive ability and socioeconomic status are partially genetic in nature. Scientific Reports. 2026;16:4315. doi:10.1038/s41598-026-37786-3 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/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/genes-iq-ses-twinlife QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-20. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Substantively audited sections covering: study design (TwinLife, MZ/DZ twins), measurement (CFT-20-R IQ at 23; education and occupation SES at 27), main results (heritability estimates; 69–98% genetic explanation of IQ–SES link; C factor minimal), pleiotropy pathways (direct and mediated), and discussion of limitations - transcript topics: TwinLife study and sample characteristics; Measurement of IQ and SES; Univariate and bivariate twin-model analyses (ACE/AE; Cholesky/related description); Genetic and environmental contributions to IQ and SES; Genetic overlap and pleiotropy pathways; Limitations and policy implications QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 6 - claims flagged for review: 0 - metadata checks passed: 4 - metadata issues found: 0 Metadata Audited: - article_doi - article_title - article_journal - license Factual Items Audited: - IQ23 heritability around 75% - SES27 heritability for education around 49% (AE) and 66% (Casmin); occupation around 32% (ACE) and 71% (AE) - Genetic factors explained 69–98% of the IQ–SES longitudinal association - Occupational SES shows up to 98% genetic overlap with IQ - Common environment (C) often minimal or dropped in best-fitting models - Two pleiotropy pathways: direct (biological) pleiotropy and mediated pleiotropy QC result: Pass.

371: Glial epigenomic dysregulation and genetic risk in tauopathies

Han et al., Nature Communications - This study uses paired single-nucleus chromatin accessibility and gene expression profiling across Alzheimer’s disease, Pick’s disease and progressive supranuclear palsy to map disease-dynamic cis-regulatory elements (CREs). Dynamic chromatin changes concentrate genetic risk in glial cell states and co-regulated regulatory modules. Integrating GWAS, sn-eQTLs and MPRA validates functional noncoding variants that tune lysosomal, lipid and vesicular pathways. Experimental CRISPRa and histology support a stress-inducible SOX10-driven glial program linked to resilience. Key terms: snATAC-seq, tauopathies, microglia, chromatin accessibility, SOX10. Study Highlights: The authors profiled matched snATAC-seq and snRNA-seq from three brain regions across AD, PiD and PSP and defined cell-type-specific CREs and 50 subclusters. Disease-dynamic peaks concentrated in glia and disproportionately capture GWAS heritability, with PiD-linked mg.C4 microglia and PSP-linked ast.C1 astrocytes identified as risk-associated states. MPRA in microglial models and sn-eQTL integration validated functional regulatory variants that converge on MEF2C/SOX10 and SNARE-centered modules affecting lysosomal, sphingolipid and trafficking pathways. CRISPRa induction of SOX10 in iPSC-derived microglia under synaptosome stress recapitulated mg.C4 programs, and RNAscope/IHC confirmed SOX10+/PLP1+ glial states in human tissue. Conclusion: Dynamic, disease-context-specific chromatin remodeling in glia concentrates genetic risk into co-regulated regulatory modules that modulate lysosomal, lipid and vesicular pathways; these modules nominate SOX10-, MEF2- and SNARE-centered circuits as candidate modulators of glial resilience across tauopathies. Music: Enjoy the music based on this article at the end of the episode. Article title: Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states First author: Han Journal: Nature Communications DOI: 10.1038/s41467-026-73007-1 Reference: Han, X., Rosenberg, G.M., Kisling, V.M. et al. Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73007-1 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/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/epigenomic-glial-genetic-risk-tauopathies QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-19. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited the transcript portions describing glial states mg.C4 microglia and ast.C1 astrocytes, regulatory networks (MEF2C/MEF2D), SOX10's role and ectopic expression, MPRA validation, CRISPRaSOX10 experiments, dynamic CREs and heritability findings, and study limitations. - transcript topics: Glial states mg.C4 microglia and ast.C1 astrocytes across tauopathies; MEF2C/MEF2D regulatory modules linking to lysosomal and phagocytic pathways; SOX10 as a stress-responsive regulator and ectopic expression in glia; MPRA validation of regulatory variants in microglia (frVars); CRISPRa SOX10 activation in hiPSC-derived microglia and recapitulation of mg.C4 programs; Dynamic CREs and GWAS heritability enrichment across disorders QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 7 - claims flagged for review: 0 - metadata checks passed: 4 - metadata issues found: 0 Metadata Audited: - article_doi - article_title - article_journal - license Factual Items Audited: - Number of nuclei and samples studied: 682,667 high-quality nuclei from 41 brains - Regions analyzed in main comparisons: Precentral Gyrus (PreCG) and insula; calcarine cortex excluded due to variability - Identification of disease-associated glial states mg.C4 microglia and ast.C1 astrocytes - Dynamic CREs enrich disease heritability, with PiD mg.C4 driving FTD heritability and PSP ast.C1 contributing PSP heritability - MEF2C/MEF2D regulatory modules link to lysosomal and phagocytic pathways in mg.C4 microglia - SOX10 is enriched/activated in mg.C4 and ast.C1 and acts as a stress-responsive regulator QC result: Pass.

370: ICMT and INPP5E enable BRAFV600E tumor growth

Yang X et al., Proceedings of the National Academy of Sciences - Genetic and pharmacologic inhibition of ICMT suppresses proliferation, invasion, and tumor growth in BRAFV600E-driven models and identifies INPP5E as an ICMT-dependent CAAX substrate whose membrane targeting supports melanoma growth. Key terms: ICMT, INPP5E, BRAFV600E, melanoma, UCM-1336. Study Highlights: ICMT genetic knockdown or pharmacologic inhibition (UCM-1336) reduced proliferation and invasion of BRAFV600E-mutant melanoma cells, decreased tumor growth in xenografts and mouse models, and retained activity in BRAF-inhibitor-resistant cells. ICMT inhibition reduced INPP5E carboxyl methylation, displaced INPP5E from membranes to the cytosol, and increased cellular PI(4,5)P2. Forced membrane targeting of INPP5E (Lyn-INPP5E) partially rescued proliferation and tumor growth during ICMT suppression. These results implicate an ICMT–INPP5E axis that supports BRAFV600E-driven tumor growth without measurable suppression of MAPK signaling. Conclusion: ICMT-dependent methylation and membrane targeting of INPP5E contribute to BRAFV600E-driven tumor growth, and ICMT inhibition (genetic or with UCM-1336) impairs melanoma growth including in BRAF-inhibitor-resistant models, highlighting ICMT as a context-dependent therapeutic vulnerability. Music: Enjoy the music based on this article at the end of the episode. Article title: ICMT supports BRAF V600E -driven tumor growth by membrane targeting of the CAAX protein INPP5E First author: Yang X Journal: Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.2601795123 Reference: Yang X, Qiao X, Schmidt S, et al. ICMT supports BRAFV600E-driven tumor growth by membrane targeting of the CAAX protein INPP5E. PNAS. 2026;123(20):e2601795123. doi:10.1073/pnas.2601795123 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/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/icmt-inpp5e-brafv600e-membrane-targeting QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-18. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited sections describing ICMT/CAAX processing, INPP5E as an ICMT substrate, membrane targeting and PI(4,5)P2 effects, rescue experiments, in vitro/in vivo models, and therapeutic implications. - transcript topics: ICMT and CAAX protein processing; INPP5E as an ICMT substrate and its membrane localization; Impact of ICMT inhibition on BRAFV600E melanoma cell proliferation and invasion; MAPK signaling independence from ICMT inhibition; In vivo models and genetic/pharmacologic ICMT suppression; Rescue experiments with Lyn-INPP5E and rescue implications QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 6 - claims flagged for review: 0 - metadata checks passed: 4 - metadata issues found: 0 Metadata Audited: - article_doi - article_title - article_journal - license Factual Items Audited: - ICMT inhibition reduces BRAFV600E-driven melanoma cell proliferation and invasion in vitro and tumor growth in vivo. - INPP5E is an ICMT-dependent CAAX substrate; ICMT inhibition reduces INPP5E methylation and displaces it from membranes. - Displacement of INPP5E increases plasma membrane PI(4,5)P2, disrupting signaling and contributing to tumor cell death. - Forced membrane targeting of INPP5E (LYN-INPP5E) partially rescues proliferation and tumor growth during ICMT suppression. - Nontransformed fibroblasts show less sensitivity to ICMT inhibition, indicating a therapeutic window. - MEK/ERK phosphorylation is not reduced by ICMT inhibition, indicating a MAPK-independent mechanism. QC result: Pass.