Base by Base

️ Episode 198: Mechanical Confinement and the Shape-Shifting Life of Melanoma Cells In this episode of PaperCast Base by Base, we explore how physical forces in the tumor microenvironment can push melanoma cells to switch from a pigment-producing, proliferative state into an invasive, drug-tolerant one, focusing on new work that links mechanical confinement, chromatin remodeling, and neuronal-like programs in cancer. Study Highlights:Using a zebrafish model of BRAFV600E-driven melanoma together with human tumor samples and single-cell transcriptomics, the authors identify a subpopulation of tumor cells at the tumor–microenvironment interface that displays elongated nuclei and a gene expression program resembling undifferentiated, neuron-like cells. In vitro confinement of human melanoma cells under a polydimethylsiloxane piston recapitulates this interface state, triggering assembly of a perinuclear cage of acetylated microtubules that protects the nucleus from mechanical stress. Mechanical confinement selectively upregulates the chromatin-bending protein HMGB2, whose increased residence time on chromatin opens neuronal and invasive gene loci and engages pathways such as Notch and BRN2 that drive a switch toward an invasive phenotype. Genetic disruption of HMGB2 in zebrafish melanomas and human melanoma cells shifts the balance back toward proliferation with larger but less invasive tumors, whereas HMGB2 overexpression enhances invasion and tolerance to BRAF and MEK inhibition in mouse xenografts. Conclusion:Mechanical confinement within the tumor microenvironment can rewire melanoma cells through HMGB2-dependent chromatin remodeling to favor an invasive, neuronal-like and drug-tolerant state over purely proliferative growth. Music:Enjoy the music based on this article at the end of the episode. Reference:Hunter MV, Joshi E, Bowker S, Montal E, Ma Y, Kim YH, Yang Z, Tuffery L, Li Z, Rosiek E, Browning A, Moncada R, Yanai I, Byrne H, Monetti M, de Stanchina E, Hamard P-J, Koche RP, White RM. Mechanical confinement governs phenotypic plasticity in melanoma. Nature. 2025;647:517–527. https://doi.org/10.1038/s41586-025-09445-6 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 websiteBase by Base – https://basebybase.com/ On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 163: Animal origins: looping back in time In this episode of PaperCast Base by Base, we explore how chromatin folding mechanisms emerged alongside animal evolution, focusing on a Spotlight article that synthesizes high-resolution 3D genome maps across unicellular relatives of animals and early-branching metazoans to probe when enhancer–promoter looping first appeared. Study Highlights:This Spotlight reviews evidence from micro-C datasets spanning ichthyosporeans, filastereans, choanoflagellates, sponges, ctenophores, placozoans, and cnidarians, showing that broad A/B-like chromatin compartments and, crucially, enhancer–promoter chromatin loops are features that arise within animals rather than in their unicellular relatives. It emphasizes that loops are readily detected in early metazoans such as ctenophores, placozoans, and cnidarians, while sponges show weaker or absent looping signals, hinting at lineage-specific trajectories or possible secondary loss. The article highlights unusual promoter hubs in placozoans, where hundreds of transcription start sites cluster, potentially coordinating housekeeping expression programs. Mechanistically, ctenophores appear to use abundant C2H2 zinc-finger proteins that bind unmethylated motifs at loop anchors, suggesting alternative loop-formation strategies distinct from the CTCF-driven loop extrusion and insulated TAD architecture characterized in vertebrates. Together, these observations argue that chromatin loops emerged with complex gene regulation in animals and diversified across lineages instead of following a single universal mechanism. Conclusion:Chromatin looping likely originated at the dawn of animal life and diversified across lineages, underpinning the rise of complex gene regulation before the canonical, CTCF-insulated TAD architecture seen in many bilaterians. Reference:Matar, O., & Marlétaz, F. (2025). Animal origins: looping back in time. Trends in Genetics. https://doi.org/10.1016/j.tig.2025.06.013 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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/ Episode Slug: animal-origins-looping-back-in-time Keywords: chromatin loops; animal evolution; Micro-C; ctenophores; enhancer–promoter interactions

️ Episode 243: Genome-wide UVB GxE study finds 162 vitamin D variants In this episode of PaperCast Base by Base, we explore A GWIS of 338,977 UK Biobank White British participants using a cumulative weighted ambient UVB measure identified 307 independent loci for 25-hydroxyvitamin D, including 162 novel variants Study Highlights:The study linked a cumulative and weighted ambient UVB (CW-D-UVB) dose from TEMIS to each participant’s residence and blood draw date to model gene-environment interaction on standardized log-transformed 25OHD in 338,977 White British UK Biobank participants. Genome-wide marginal, interaction, and joint tests identified 307 independent variants associated with 25OHD, 162 of which were novel to prior GWAS. SNP-heritability increased across CW-D-UVB quintiles from 8.48% in the lowest to 15.56% in the highest and was higher in participants reporting ≥3 hours outdoors. Functional annotation implicated known vitamin D genes, glucuronidation and lipid metabolism pathways, and circadian clock genes including BMAL1 and NPAS2, with replication showing concordant effect directions in European, LURIC, and ORCADES cohorts Conclusion:Incorporating a precise ambient UVB exposure measure increased power to detect genetic effects on vitamin D status and revealed GxE interactions linking vitamin D biology with lipid metabolism and circadian regulation Music:Enjoy the music based on this article at the end of the episode. Reference:Shraim R, Timofeeva M, Wyse C, van Geffen J, van Weele M, Romero-Ortuno R, Lopez LM, Pilz S, März W, Fletcher BS, Kleber ME, Wilson JF, Theodoratou E, Dunlop MG, McManus R, Zgaga L. Genome-wide gene-environment interaction study uncovers 162 vitamin D status variants using a precise ambient UVB measure. Nat Commun. 2025;16:10774. https://doi.org/10.1038/s41467-025-65820-x 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/uvb-gxe-vitamin-d-variants Episode Slug: uvb-gxe-vitamin-d-variants Keywords: vitamin D, gene-environment interaction, ambient UVB, GWAS, circadian rhythm

️ Episode 242: AAV9-fcMISv2 gene therapy prevents pregnancy in female cats In this episode of PaperCast Base by Base, we explore A single intramuscular injection of an AAV9 vector encoding feline anti‑Müllerian hormone (fcMISv2) in prepubertal kittens produced sustained supraphysiological AMH, was well tolerated, and prevented breeding‑induced ovulation and pregnancy in adult females Study Highlights:Twelve 2–3 month-old kittens received a single IM dose of AAV9-fcMISv2 (low or high dose) or empty AAV9 and were monitored for up to 21 months for females and 10 months for males. Treated animals showed rapid viral clearance, no clinically significant systemic inflammation or growth impairment, and no anti‑AMH antibody response. Females developed sustained elevated AMH, had reduced fecal estrogen and progestogen metabolites, increased circulating LH, lacked luteal phases, displayed altered estrous behavior, and none of the treated females became pregnant during a year-later 4‑month mating trial. Males completed puberty, maintained normal testis development, semen parameters, and in vitro fertilizing capacity, indicating preserved male fertility. Conclusion:Prepubertal intramuscular delivery of AAV9-fcMISv2 is a safe, durable, female-specific sterilant in domestic cats that prevents breeding-induced ovulation and pregnancy while sparing male reproductive function Music:Enjoy the music based on this article at the end of the episode. Reference:Godin P., Nagykery N., Sicher N., Barnes J. L., Miller A. G., Bunner C., Thompson A. K., Kano M., Gao G., Wang D., Donahoe P. K., Rhodes L., Brake D. A., Conlon T. J., Swanson W. F., Vansandt L. M. & Pépin D. Gene therapy delivery of anti‑Müllerian hormone in prepubertal female domestic cats induces long-term sterilization. Nat Commun. 2025;16:10747. https://doi.org/10.1038/s41467-025-65780-2 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. Keywords: gene therapy, anti-Müllerian hormone, feline sterilization, adeno-associated virus, population control Chapters (00:00:00) - A single shot, long term contraceptive for cats(00:05:29) - The AMH treatment in cats(00:07:31) - AMH completely abrogated ovulation in cats(00:08:53) - Gene therapy for women's uterine health(00:09:31) - African cats: Sterilization by blocking ovulation(00:12:53) - Signal to Stillness

️ Episode 241: Wagyu T2T reveals a cattle X neocentromere In this episode of PaperCast Base by Base, we explore A telomere-to-telomere Wagyu assembly uncovers a natural neocentromere on the cattle X formed by inverted repeats and transposable element expansion, adds hundreds of new genes, and improves variant discovery Study Highlights:The UOA_Wagyu_1 haplotype-resolved assembly includes a complete X chromosome and four T2T autosomes, adding 431 Mb relative to the ARS-UCD2.0 reference and annotating 738 new protein-coding genes. The cattle X centromere spans ~12 Mb and is a natural neocentromere composed mainly of highly identical inverted repeats and transposable elements, lacking canonical bovine satellite arrays and showing low CENP-A signal. The BTAX centromere exhibits CpG depletion and elevated TpG consistent with TE expansion followed by methylation and CpG deamination, and all 37 centromeric protein-coding genes are expressed in testes. Using UOA_Wagyu_1_Y increased mapping rates for Wagyu reads and enabled discovery of 49,610 structural variants from 20 animals, revealing Wagyu-specific SV and PAV hotspots overlapping genes enriched for olfactory transduction. Conclusion:A breed-specific T2T cattle genome reveals a dynamic, TE-rich X neocentromere with testis-expressed genes and substantially improves structural variant discovery for Wagyu populations Music:Enjoy the music based on this article at the end of the episode. Reference:Pineda PS, MacPhillamy C, Ren Y, Chen T, Zhong L, Adelson DL, Dessaix C, Perez-Silva J, Haggerty L, Martin FJ, Bottema CDK, Pitchford WS, Rosen BD, Smith TPL, Low WY. Insights into natural neocentromere evolution from a cattle T2T X chromosome. Nature Communications. 2025;16:10745. https://doi.org/10.1038/s41467-025-65778-w 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/wagyu-t2t-x-neocentromere Episode Slug: wagyu-t2t-x-neocentromere Keywords: cattle genomics, neocentromere, centromere evolution, telomere-to-telomere, structural variants Chapters (00:00:00) - Finding the dark matter of cattle genetics(00:05:26) - The cattle genome: a mutational puzzle(00:10:09) - Strange centromere on the cattle X chromosome

️ Episode 240: CYFIP1 controls cortical axon development by modulating calcium In this episode of PaperCast Base by Base, we explore Reduction of CYFIP1 delays callosal axon growth and arborization by lowering intracellular calcium and impairing mitochondrial function Study Highlights:In vivo, Cyfip1+/- mice show delayed callosal axon growth at P5 and reduced axonal branching during P15 arborization that normalizes by P30. Cyfip1+/- cortical neurons have reduced cytosolic and mitochondrial calcium, larger and elongated mitochondria, increased mitochondrial density and motility, and decreased mitochondrial membrane potential and ATP at early stages. CYFIP1 associates with Hu proteins and binds mRNAs encoding Cav alpha-1 subunits (Cacna1c, Cacna1e, Cacna1i), stabilizing those transcripts and maintaining membrane protein levels in developing neurons and axons. Loss of CYFIP1 accelerates decay of these channel mRNAs, leading to reduced Cav protein abundance in axons and lower calcium availability. Restoring intracellular calcium with ionomycin or activating L-type channels (Bay-K-8644, nefiracetam) rescues axonal growth and mitochondrial defects in Cyfip1+/- neurons Conclusion:CYFIP1 ensures timely cortical callosal development by stabilizing mRNAs for voltage-gated calcium channel subunits to maintain intracellular calcium and mitochondrial function, and its haploinsufficiency may contribute to connectivity deficits linked to neurodevelopmental disorders Music:Enjoy the music based on this article at the end of the episode. Reference:Ricci C, Midroit MJ, Caicci F, Achsel T, Domínguez-Iturza N, Bagni C. CYFIP1 governs the development of cortical axons by modulating calcium availability. Nature Communications. 2025;16:10764. https://doi.org/10.1038/s41467-025-65801-0 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Keywords: cyfip1, axon development, calcium, mitochondria, callosal connectivity Chapters (00:00:00) - Deep Dive: The brain's dysfunctional wiring(00:02:10) - CYFIP1 governs the development of cortical axons by(00:07:16) - The bottleneck in MRNA production(00:08:03) - CIFIP1 deficiency in neurodevelopmental disorders(00:13:06) - CY FIP1 dysregulation in the brain

️ Episode 239: Genomic Adaptations of the Svalbard Reindeer In this episode of PaperCast Base by Base, we explore Comparative whole-genome analyses identify 150 differentiated genomic regions and candidate genes linked to fat metabolism, energy conservation, cold tolerance, reduced body size, fur morphology, and circadian rhythm that likely underpin Svalbard reindeer adaptation to the High Arctic Study Highlights:The authors sequenced and analyzed 62 reindeer genomes from Svalbard, mainland Norway, mainland Russia, and Novaya Zemlya using three complementary approaches: population branch statistic scans, annotation of high-frequency derived coding variants, and copy number variant analysis. They identified 150 genomic regions with 120 annotated candidate genes enriched for functions related to methylglyoxal metabolism, DNA repair, transport, metabolism, and microtubule extension. Candidate genes and structural variants implicate pathways for fat storage and fasting endurance, insulin and leptin-related energy regulation, brown adipose thermogenesis, fur and skin development, eye and circadian function, and genes associated with reduced body and limb size. Results show no single gene set detected by all methods, indicating a complex genomic architecture where selection, drift from historical bottlenecks, and structural variation contribute to the Svalbard phenotype. Conclusion:Multiple genomic regions and candidate genes involved in energy metabolism, thermoregulation, and morphology show putative signatures of adaptation that likely enabled Svalbard reindeer to persist in the High Arctic despite low genetic diversity Music:Enjoy the music based on this article at the end of the episode. Reference:Dussex N, Ersmark E, Hansen BB, Bieker VC, Sun X, Le Moullec M, Røed KH, Speakman JR, Loe LE, Dalén L, Martin MD. The Genomic Basis of the Svalbard Reindeer’s Adaptation to an Extreme Arctic Environment. Genome Biol Evol. 2025;17(9):evaf160. https://doi.org/10.1093/gbe/evaf160 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Keywords: Svalbard reindeer, genomics, adaptation, thermoregulation, energy metabolism Chapters (00:00:00) - How do animals evolve to survive in the Arctic?(00:04:09) - How did the Svalbard reindeer evolve so quickly?(00:09:24) - Adaptation to cold and fat(00:11:10) - The story of the Svalbard Reindeer(00:15:41) - Winter Songs for Creatures

️ Episode 238: Germline polymorphisms shape antibody light chain repertoires In this episode of PaperCast Base by Base, we explore Long-read sequencing of IGK and IGL paired with AIRR-seq shows that common germline SNVs, SVs, and alleles drive inter-individual differences in light chain gene usage and CDR3 properties Study Highlights:The authors combined targeted long-read genomic sequencing of IGK and IGL in 177 donors with matched AIRR-seq (IGK n=164, IGL n=168) to generate phased SNV, SV, and allele callsets and personalized germline databases. Cis guQTL analysis identified 2,352 variants in the unmutated IGK repertoire linked to usage changes in 21 IGKV and 3 IGKJ genes, and 911 variants in IGL linked to 22 IGLV and 3 IGLJ genes, indicating germline variation affects >70% of light chain genes. Lead variants mapped to intergenic regions, RSSs, coding exons and structural variants, with examples including a premature stop in IGKV2-29, a K50D missense in IGKV1-5, RSS spacer changes in IGLV3-16, and copy-number SVs that alter gene usage. Genetic effects were stronger in the antigen-naïve repertoire, associated with shifts in encoded V/J alleles and CDR3 physicochemical properties, and IGK exhibited larger LD blocks and coordinated multi-gene usage compared with IGL. Conclusion:Germline polymorphisms across IGK and IGL establish reproducible baseline differences in light chain gene availability and amino acid composition that likely influence antibody-mediated responses. Music:Enjoy the music based on this article at the end of the episode. Reference:Engelbrecht E, Rodriguez OL, Lees W, Vanwinkle Z, Shields K, Schultze S, Gibson WS, Smith DR, Jana U, Saha S, Peres A, Yaari G, Smith ML, Watson CT. Germline polymorphisms in the immunoglobulin kappa and lambda loci underpinning antibody light chain repertoire variability. Nat Commun. 2025. https://doi.org/10.1038/s41467-025-66759-9 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Keywords: immunoglobulin-kappa, immunoglobulin-lambda, germline-variation, antibody-repertoire, long-read-sequencing Chapters (00:00:00) - How your genetic blueprint shapes your immunity(00:01:38) - Personal genetics of the human genome(00:05:13) - What Did Genomic Personalization Reveal About the Immunity(00:08:21) - How genetic variation affects the way your body recognizes molecules

️ Episode 237: Tracing enteric pathogens in Africa with metagenomics and WGS In this episode of PaperCast Base by Base, we explore This study combines whole-genome sequencing and metagenomics to map the diversity, abundance, and genomic relationships of enteric foodborne pathogens across human, animal, food and environmental samples in four African LMICs Study Highlights:The project sampled 3,417 items across Ethiopia, Mozambique, Nigeria and Tanzania between 2019 and 2023 and applied culture-based WGS and metagenomic sequencing. Of 446 recovered isolates, 380 high-quality genomes were analyzed (207 E. coli, 138 Salmonella spp., 24 Campylobacter spp., 11 Shigella spp.), and 139 metagenomes passed QC for community profiling. Pathogen distributions were geographically stable over time, with genomic clustering showing closely related isolates across distinct sources consistent with potential transmission routes. Metagenomics revealed dominant genera such as Escherichia, Enterococcus and Bifidobacterium, recovered 13 high-quality MAGs (12 E. coli, 1 Campylobacter), and provided complementary population-level insights though MAGs rarely reached strain-level identity with cultured isolates. Conclusion:Combining targeted environmental and food-chain sampling with WGS and metagenomic sequencing strengthens surveillance and source-tracing of foodborne enteric pathogens in resource-limited African settings Music:Enjoy the music based on this article at the end of the episode. Reference:Thystrup C, Gobena T, Salvador EM, Fayemi OE, Kumburu H, Buys EM, Gichure J, Moiane BT, Belina D, Hugho EA, Faife S, Ogunbiyi TS, Akanni G, Ayolabi CI, Mmbaga B, Thomas KM, Pires SM, Njage PMK, Hald T. Using metagenomics and whole-genome sequencing to characterize enteric pathogens across various sources in Africa. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66400-9 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Keywords: metagenomics, whole-genome sequencing, foodborne pathogens, one-health, surveillance Chapters (00:00:00) - Meeting the challenges of diarrheal disease tracking(00:05:52) - WGS findings on diarrheal disease(00:06:53) - E. Coli, Salmonella(00:08:01) - The wide angle lens of metagenomic science(00:13:19) - Getting it out there: pathogens in our water(00:14:25) - Follow the Signal

️ Episode 236: XPD translocation and genetic disease etiology In this episode of PaperCast Base by Base, we explore Computational modeling reveals how ATP-driven conformational cycles of the XPD helicase drive directional 5′→3′ translocation on single-stranded DNA and how mutations disrupt this process to cause disease Study Highlights:The authors combined molecular dynamics, partial nudged elastic band path optimization, transition path sampling, and Markov state modeling to map seven metastable on-path states that define XPD’s ATPase cycle. ATP binding and hydrolysis drive reciprocal rotations of the RecA2 and Arch domains, transmitted via a spring helix and spindle helix, that alternate DNA affinity at two defined constrictions at the 5′ and 3′ ends of the DNA-binding groove. Translocation proceeds in two phases: RecA2-driven sliding of ssDNA through Constriction 1 followed by ATP hydrolysis, constriction switching and sliding through Constriction 2, advancing one nucleotide per ATP. Mapping of missense mutations shows clustering of disease-associated residues at DNA- and ATP-binding sites and classifies mutations that impair DNA binding, ATPase function, or allosteric domain dynamics Conclusion:A detailed mechanistic map links XPD’s nucleotide-dependent conformational switching to directional ssDNA translocation and explains how perturbations of key residues underlie XP, CS, and TTD phenotypes Music:Enjoy the music based on this article at the end of the episode. Reference:Paul T, Yan C, Derdeyn-Blackwell G, Ivanov I. Translocation mechanism of xeroderma pigmentosum group D protein on single-stranded DNA and genetic disease etiology. Nat Commun. 2025. https://doi.org/10.1038/s41467-025-66834-1 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Keywords: XPD, DinG, ssDNA translocation, nucleotide excision repair, disease mutations Chapters (00:00:14) - Leading the charge in the DNA repair process(00:04:33) - How XPD moves forward in the DNA(00:07:49) - How does XPD pull the DNA forward?(00:10:36) - How XPCS mutations disrupt the ATP engine(00:12:46) - XPD

️ Episode 235: Maternal H3K9 methyltransferases control aRMAE in C. elegans In this episode of PaperCast Base by Base, we explore Using dual-color reporters in C. elegans, the study shows maternal H3K9 methyltransferases MET-2 and SET-25 antagonistically regulate autosomal random monoallelic expression initiated in the early embryo Study Highlights:Dual-color fluorescent reporter alleles in C. elegans intestine cells enabled single-cell quantification of allele expression and a targeted screen for aRMAE regulators. MET-2/SETDB1, with LIN-65 and ARLE-14, acts maternally in the 8-cell E-cell to prevent monoallelic expression, while SET-25/SUV39 with HPL-2 and LIN-61 promotes allele silencing. Catalytic SET domains of both MET-2 and SET-25 are required for their opposing activities, and loss of MET-2 increases persistent but non-heritable monoallelic expression whereas loss of SET-25 causes biallelic expression. Reciprocal crosses and genetic interactions indicate these maternal H3K9 HMTs set early embryonic histone states that are propagated through somatic divisions to shape tissue-wide allele expression. Conclusion:Maternal MET-2 and SET-25 establish competing H3K9-related chromatin states in the early embryo that bias autosomal alleles toward persistent somatic monoallelic or biallelic expression Music:Enjoy the music based on this article at the end of the episode. Reference:Sands, B., Yun, S.R., Oshima, J. et al. Maternal histone methyltransferases antagonistically regulate autosomal random monoallelic expression (aRMAE) in C. elegans. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66501-5 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Keywords: histone-methyltransferase, aRMAE, MET-2, SET-25, c-elegans Chapters (00:00:00) - How do maternal histone methyltransferases regulate DNA health?(00:05:14) - The epigenetic tug of war in the worm(00:09:11) - Maternal DNA silencing(00:14:27) - Half the Story

️ Episode 234: MTHFR genotype and methionine metabolism predict COVID-19 severity In this episode of PaperCast Base by Base, we explore IMPACC longitudinal metabolomics and genomics analyses show that disruptions in one‑carbon/methionine metabolism together with MTHFR C677T genotype at hospital admission improve prediction of severe COVID‑19 and long COVID risk Study Highlights:IMPACC profiled plasma metabolites (global and targeted) from over 1,000 hospitalized COVID-19 patients and identified early alterations in one‑carbon metabolism, with emphasis on the methionine cycle. Methionine‑sulfoxide and S‑adenosylhomocysteine (SAH) were elevated in patients with more severe clinical trajectories and changed over serial visits. The common hypomorphic MTHFR C677T (AA) genotype associated with distinct methionine‑cycle metabolite profiles and, when combined with baseline methionine, methionine‑sulfoxide, and SAH levels, significantly improved mortality prediction versus genotype alone. The combined genotype–metabolite factor also stratified risk of long COVID across patient‑reported outcome clusters. Conclusion:Integrating MTHFR C677T status with early plasma methionine‑cycle metabolite measurements can enhance early risk stratification for severe COVID‑19 and long COVID. Music:Enjoy the music based on this article at the end of the episode. Reference:Petrova B, Syphur C, Montgomery RR, Levy O, Diray‑Arce J, Kleinstein SH, Kanarek N, Culhane AJ, Chen J, et al. MTHFR allele and one‑carbon metabolic profile predict severity of COVID‑19. Proc Natl Acad Sci U S A. 2025;122(51):e2509118122. https://doi.org/10.1073/pnas.2509118122 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/mthfr-methionine-covid-risk Episode Slug: mthfr-methionine-covid-risk Keywords: mthfr, one-carbon metabolism, methionine, metabolomics, long covid

️ Episode 233: Mechanistic basis of NuA3 recognition and H3K14 acetylation In this episode of PaperCast Base by Base, we explore Cryo-EM structures of the yeast NuA3 complex reveal how a cooperative Sas3–Nto1 binding cleft recognizes the H3 tail and directs acetylation of H3K14 Study Highlights:The authors report cryo-EM structures of NuA3 in apo, acetyl-CoA-bound, and acetyl-CoA plus H3 tail-bound states at ~3.7, 3.1, and 3.2 Å resolution respectively. The histone H3 tail binding cleft is formed cooperatively by the catalytic subunit Sas3 and the non-catalytic subunit Nto1, with a hydrophobic pocket engaging H3 residues 9–12 and a polar network contacting the backbone of residues 12–15, notably Gly13. Acetyl-CoA binding induces conformational changes in a histone-engaging loop and a CoA-engaging helix that expand the cleft and position catalytic residues Cys418 and Glu452 between H3K14 and the acetyl donor. Mutational and biochemical assays show L369R abolishes HAT activity, N354A partially reduces activity, and a G13R peptide is poorly acetylated, supporting the structural basis for H3K14 specificity and recruitment by H3K4me3/H3K36me3 readers. Conclusion:The structures define a cooperative Sas3–Nto1 recognition mechanism and Gly13-dependent substrate geometry that underlie NuA3 specificity for H3K14 acetylation Music:Enjoy the music based on this article at the end of the episode. Reference:Shi, W., Zhao, L., Wang, Y. et al. Mechanistic insights into histone recognition and H3K14 acetylation by the NuA3 histone acetyltransferase complex. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67049-0 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Keywords: NuA3, histone acetylation, H3K14, cryo-EM, Sas3-Nto1

️Episode 232: Lamin A/C steers fork restart via H3K9me3 and PARylation In this episode of PaperCast Base by Base, we explore Nucleoplasmic Lamin A/C, together with LAP2α, enforces active replication fork slowing during mild replication stress by promoting local H3K9me3 and ADP-ribosylation to restrain RECQ1-mediated restart and protect genome stability Study Highlights:Lamin A/C dynamically associates with replication factories throughout the nucleus and its acute depletion abolishes stress-induced fork slowing and increases chromosomal breakage. Loss of nucleoplasmic Lamin A/C or LAP2α reduces poly-ADP-ribosylation (PAR) at nascent DNA, leading to untimely RECQ1-dependent restart of reversed forks. Mild replication stress induces accumulation of H3K9me3 at replication forks, and Lamin A/C is required to maintain this mark by preventing its removal by the demethylase KDM3A/JMJD1A. Inhibiting G9a to prevent H3K9 methylation phenocopies Lamin A/C loss, reducing PAR at forks and deregulating RECQ1 restart, whereas PARG inhibition or KDM3A downregulation restores PAR levels and fork slowing. Conclusion:Nucleoplasmic Lamin A/C maintains local chromatin compaction and PARylation at replication factories to limit RECQ1 activity, enforce fork slowing under mild stress, and preserve genome stability Music:Enjoy the music based on this article at the end of the episode. Reference:Cherdyntseva V, Paulson J, González-Acosta D, Ubieto-Capella P, Rodrigues M, Aouami M, Adakli S, Gagné J-P, Bakker C, Poirier GG, Taneja N, Lopes M. Nucleoplasmic Lamin A/C controls replication fork restart upon stress by modulating local H3K9me3 and ADP-ribosylation levels. Nat Commun. 2025. https://doi.org/10.1038/s41467-025-66098-9 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️Episode 231: Transcription start sites as a germline mutational hotspot In this episode of PaperCast Base by Base, we explore This study identifies a pronounced germline mutational hotspot centered on transcription start sites (TSSs) driven in part by early embryonic mosaic variants and transcription-associated DNA damage Study Highlights:Extremely rare variants show a localized excess of non(CpG > TpG) mutations around TSSs extending several hundred base pairs, reaching ~35% enrichment at the 100-bp scale and ~14% at 1 kb. The hotspot is largely absent from de novo mutation calls because early mosaic variants are significantly enriched downstream of the TSS and are often filtered from family sequencing data. Regression and feature analyses link the TSS excess to divergent transcription, RNA polymerase II stalling, R-loop formation and somatic (mitotic) double-strand breaks rather than meiotic PRDM9-associated breaks. Mutational signature decomposition implicates non-canonical DSB repair (including TMEJ) and transcription-associated processes, and the hotspot preferentially affects genes related to cancer and developmental phenotypes. Conclusion:Transcription initiation regions are focal points of heritable variation shaped by early-development mosaicism and transcription-linked mitotic DNA damage, with implications for disease genetics and evolutionary constraint Music:Enjoy the music based on this article at the end of the episode. Reference:Cortés Guzmán M, Castellano D, Serrano Colomé C, Seplyarskiy V, Weghorn D. Transcription start sites experience a high influx of heritable variants fueled by early development. Nat Commun. 2025;16:10120. https://doi.org/10.1038/s41467-025-66201-0 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️Episode 230: MIDEAS Y654S hyperactivates MiDAC in a dominant neurodevelopmental syndrome In this episode of PaperCast Base by Base, we explore A recurrent de novo MIDEAS p.Tyr654Ser variant disrupts an autoinhibitory loop in the MiDAC complex, increasing HDAC1 deacetylase activity and causing a multisystem neurodevelopmental disorder Study Highlights:Two unrelated probands carry the same de novo heterozygous MIDEAS p.Tyr654Ser variant and present with speech delay, progressive joint contractures, facial dysmorphism and gastrointestinal dysmotility. A 2.9 Å cryo-EM structure shows Y654 lies in a conserved loop of MIDEAS that covers the HDAC1 active site and positions I659 into the active site channel. The Y654S change creates an STP CDK consensus site that is highly phosphorylated and leads to displacement of the inhibitory loop, producing a 3–5-fold increase in MiDAC deacetylase activity in vitro. Patient fibroblast transcriptomes display largely reciprocal gene expression changes compared with MiDAC-depleted cells, and MiDAC loss upregulates MAP2K6 and MAP2K3 implicating p38 MAPK pathway involvement. Conclusion:MIDEAS p.Tyr654Ser is a dominant monogenic cause of a neurodevelopmental syndrome driven by hyperactivity of the MiDAC HDAC complex Music:Enjoy the music based on this article at the end of the episode. Reference:Sirvydis K., Fairall L., Knottnerus SJG., Gonchar O., Muskett FW., Jukes-Jones R., van Brussel L., van de Geer E., van Gassen K., Badenhorst P., van Hasselt PM., van Jaarsveld RH., Schwabe J.W.R., et al. A de novo missense variant in MIDEAS results in increased deacetylase activity of the MiDAC HDAC complex causing a neurodevelopmental syndrome. Nat Commun. 2025;16:10472. https://doi.org/10.1038/s41467-025-65472-x 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️Episode 229: Inhibiting PCBP2 condensates in Alzheimer’s In this episode of PaperCast Base by Base, we explore Elevated PCBP2 forms liquid-like condensates that sequester mitochondrial and RNA-binding proteins, stabilize BACE1 mRNA, and promote amyloid pathology while the small molecule CN-0928 reduces PCBP2 via INTS1 to lower Aβ and improve cognition in AD models Study Highlights:PCBP2 protein is increased in AD patient brains and AD mouse models and forms enlarged, dynamic cytoplasmic condensates that undergo LLPS in vitro and in cells. PCBP2 condensates concentrate mitochondrial proteins and RNA-binding/NMD factors including UPF1, correlating with disrupted mitochondrial morphology, increased ROS, and reduced mitochondrial respiration. PCBP2 stabilizes BACE1 mRNA by sequestering NMD components into condensates and thereby impairs 3′UTR-dependent decay. The small molecule CN-0928 binds INTS1 at Arg-1404, lowers PCBP2 transcription and protein levels, reduces condensates, decreases BACE1 and Aβ, and improves cognitive performance in 5×FAD mice Conclusion:Targeting PCBP2 biomolecular condensates via INTS1 with CN-0928 offers a novel strategy to mitigate mitochondrial dysfunction and BACE1-driven amyloidogenesis in Alzheimer’s disease Music:Enjoy the music based on this article at the end of the episode. Reference:Wang L, Xie X-Y, Pan Q-L, Zhang J, Zhou G-F, Zhang Q-L, Yan X-X, Xiang Y, Li C-L, He Y, Xiang X-J, Deng X-J, Wang Y-J, Zhou J-Y, Nie S & Chen G-J. Pharmacologic inhibition of PCBP2 biomolecular condensates relieves Alzheimer’s disease. Nat Commun. 2025;16:10514. https://doi.org/10.1038/s41467-025-65547-9 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 228: Two non-competing H3N2 stem antibodies reveal evolving antigenicity In this episode of PaperCast Base by Base, we explore Structural and functional characterization of two group 2 H3 HA stem antibodies, 2F02 and AG2-G02, shows distinct non-overlapping epitopes, protection in mice, and antigenic changes driven by HA2 position 32 that limit AG2-G02 binding Study Highlights:Cryo-EM structures show 2F02 targets the central stem epitope while AG2-G02 targets the lower stem epitope and the two can bind concurrently to an HA trimer. Both antibodies neutralize diverse H3 strains in vitro and provide prophylactic protection in mice, with Fc-mediated effector functions contributing to in vivo efficacy. AG2-G02 binding is lost to recent human H3N2 HAs carrying R32 at HA2, whereas T32 or I32 permit binding. Human plasma binding profiles mirror the historical shift from T32 to I32 to R32, indicating altered population antigenicity of the lower stem over time. Conclusion:Natural evolution at HA2 position 32 has changed the antigenicity of the H3N2 HA lower stem, impacting binding of certain group 2 stem antibodies and informing vaccine design strategies Music:Enjoy the music based on this article at the end of the episode. Reference:Gopal AB, Lv H, Ouyang WO, Teo QW, Luo Y, Tang YS, Luo M, Mok CKP, Wu NC. Characterization of two non-competing antibodies to influenza H3N2 hemagglutinin stem reveals its evolving antigenicity. Nat Commun. 2025;16:10557. https://doi.org/10.1038/s41467-025-65595-1 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 227: 1q gain enables rescue of aneuploid hESCs during RPE differentiation In this episode of PaperCast Base by Base, we explore This study shows that spontaneous RPE differentiation eliminates most aneuploid human pluripotent stem cells but permits expansion of cells with chromosome 1q gains when they are co-cultured with wild-type cells Study Highlights:Large-scale single-cell genomics revealed pervasive low-grade mosaicism in genetically balanced hPSC cultures, with 3–6% of cells carrying various aneuploidies. During undirected RPE differentiation most aneuploid lineages are purged, except for cells bearing gains of chromosome arm 1q which persist. 1q-gain cells only complete neural/RPE specification when co-cultured with wild-type cells that provide paracrine ligands and induce neuroectodermal regulons, enabling rescued differentiation trajectories. Rescued RPE1q cells show comparable RPE marker expression but display transcriptional signs of aneuploidy-related stress and can outcompete wild-type and other aneuploid cells, whereas 20q11.21 gains, iso20q and trisomy 20 generally fail to be rescued. Conclusion:Spontaneous RPE differentiation acts as a selective bottleneck removing most aneuploid cells but permits expansion of 1q-gain clones via wild-type co-culture rescue, underscoring the importance of genomic surveillance for hPSC-derived therapies Music:Enjoy the music based on this article at the end of the episode. Reference:Couvreu de Deckersberg E, Lei Y, Krivec N, Huyghebaert A, Duong MC, Janssens C, Regin M, Tsuiko O, Movahedi K, Verhulst S, van Grunsven LA, Sermon K, Al Delbany D, Spits C. 1q gain bypasses the selective barrier against aneuploidy in RPE differentiation via wild-type co-culture rescue. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66766-w 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode 226: FGF4 protects podocytes in diabetic kidney disease In this episode of PaperCast Base by Base, we explore This study shows that podocyte-derived FGF4 is reduced in DKD and that recombinant FGF4 preserves podocyte survival and glomerular function in diabetic models via FGFR1-AMPK-FOXO1 signaling Study Highlights:FGF4 expression is downregulated in kidneys from DKD patients and diabetic mouse models and localizes predominantly to podocytes. Podocyte-specific deletion of Fgf4 worsened albuminuria, reduced GFR, increased oxidative stress and podocyte loss in diabetic mice. Systemic treatment with a non-mitogenic recombinant FGF4 improved glucose in db/db mice, lowered UACR and BUN, reduced fibrosis, ROS and apoptosis, and restored podocyte markers in both T1D and T2D models. The protective effects of rFGF4 require podocyte FGFR1 and downstream AMPK-FOXO1 activity, as Fgfr1, Ampk, or Foxo1 podocyte knockouts abolished rFGF4 benefits. rFGF4 also reversed high glucose–induced injury and promoted nuclear FOXO1 in human podocytes and isolated human glomeruli Conclusion:FGF4 is a podocyte-derived regulator that promotes podocyte survival and mitigates DKD through FGFR1-mediated activation of the AMPK-FOXO1 axis, supporting rFGF4 as a potential therapeutic approach for diabetic kidney disease Music:Enjoy the music based on this article at the end of the episode. Reference:Wang S, Lou J, Pan B, Zhao M, Li Q, Zhou J, et al. FGF4-FGFR1 signaling promotes podocyte survival and glomerular function to ameliorate diabetic kidney disease in male mice. Nat Commun. 2025;16:10430. https://doi.org/10.1038/s41467-025-65978-4 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 Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/fgf4-podocyte-protects-kidney Episode Slug: fgf4-podocyte-protects-kidney Keywords: FGF4, FGFR1, podocyte, AMPK-FOXO1, diabetic kidney disease