Gao J et al., Nat Commun - H4 tail lysine residues drive liquid-liquid phase separation of 12‑mer nucleosome arrays, while H3 tail acetylation and the histone chaperone Nap1 increase internal dynamics and lower droplet viscosity. Key terms: Nap1, H3 acetylation, H4 acetylation, liquid-liquid phase separation, nucleosome arrays. Study Highlights:H4 tail lysine residues are the primary drivers of nucleosome array phase separation, and H4-tail acetylation prevents droplet formation. H3 tail acetylation mimic (H3KQ) and in situ H3 acetylation speed fluorescence recovery, indicating enhanced DNA–histone dynamics. Nap1 dissolves gel-like aggregates formed by tailless H3 arrays, increases nucleosome concentration inside droplets from ~326 µM to ~491 µM, and accelerates internal dynamics. STORM imaging reveals condensed droplets contain both a mobile fraction and a relatively immobile structural scaffold. Optical-tweezers microrheology identifies two relaxation components and shows Nap1 and H…

️ Episode 252: Keratinocytes to cSCC: genetic steps In this episode of PaperCast Base by Base, we explore Single-cell and spatial multi-omic profiling maps the genetic and transcriptional changes from normal keratinocytes through actinic keratoses to invasive cutaneous squamous cell carcinoma Study Highlights:Single-cell genotyping of 137 keratinocytes revealed most cells have low mutation burdens (median 1.14 mut/Mb) while keratinocytes with TP53 or NOTCH1 mutations carry substantially higher burdens. Deep panel sequencing of 16 paired actinic keratoses and adjacent cSCCs showed TERT promoter and CDKN2A mutations arise in actinic keratoses and additional events such as ARID2 loss and MAPK pathway activation delineate progression to cSCC. Many actinic keratoses were genetically unrelated to their neighboring cSCCs, indicating independent clonal origins despite spatial proximity. Spatial transcriptomics exposed intratumoral heterogeneity and enrichment of immune checkpoint molecules at…

️ Episode 251: MuSCs, laminin-α2 and LAMA2 MD In this episode of PaperCast Base by Base, we explore Activated muscle stem cells express and secrete laminin-α2 to remodel their niche, and loss of MuSC-derived laminin-α2 slows MuSC proliferation and delays regeneration in mouse models and human iPSC-derived precursors Study Highlights:Activated MuSCs upregulate Lama2 and deposit laminin-α2 around proliferating cells during early regeneration. MuSCs from Lama2-deficient dyW/dyW mice progress more slowly through S phase, accumulate in G1, and show reduced expansion ex vivo and in vivo. Transplantation of dyW/dyW MuSCs into wild-type muscle does not restore their proliferative capacity, indicating a cell-intrinsic defect. A MuSC-specific Lama2 knockout recapitulates the slower proliferation and reduces early injury-associated laminin-α2, delaying muscle repair. Isogenic human LAMA2 knockout myogenic precursors also incorporate less EdU and show transcriptional changes consistent with impai…

️ Episode 250: CIP2A–TOPBP1: Mitotic repair via MiDAS and MMEJ In this episode of PaperCast Base by Base, we explore This study shows the CIP2A-TOPBP1 complex coordinates two mitotic double-strand break repair pathways, MiDAS and MMEJ, by recruiting SLX4/SMX components and Polθ to mitotic chromatin. Study Highlights:TOPBP1 BRCT1/2 binds SLX4 phosphorylated at Thr1260, a CDK1-dependent modification that promotes recruitment of SLX4, MUS81 and ERCC1 to mitotic chromatin to drive MiDAS. CIP2A is required for mitotic chromatin localisation of both TOPBP1 and Polθ, enabling Polθ-dependent MMEJ. Loss of CIP2A impairs both MiDAS and MMEJ, increasing micronuclei, γH2AX and 53BP1 and reducing proliferation under replication stress. Pharmacological Polθ inhibition combined with disruption of the TOPBP1–SLX4 interaction further elevates genome instability and selectively limits growth of BRCA1/2-deficient cells. Conclusion:The CIP2A-TOPBP1 axis is a central mitotic DNA repair hub that integrates…

️ Episode 249: PCM1 links centrosome asymmetry to endosome dynamics In this episode of PaperCast Base by Base, we explore In developing neural progenitors PCM1 localizes to the mother centrosome and to Notch ligand-containing endosomes, promoting Par-3/dynein assembly and Rab5-to-Rab11 trafficking to bias posterior-directed endosome segregation and preserve progenitor fate Study Highlights:Pcm1 is asymmetrically enriched at the posterior mother centrosome (Cep83+) in zebrafish radial glia progenitors and is also found on central-zone Notch ligand (Dld)-containing endosomes. In vivo time-lapse imaging and expansion microscopy show Pcm1 puncta move with Dld endosomes and promote posterior-directed polarized dynamics. Loss of pcm1 disrupts Rab5b-to-Rab11a trafficking, reduces Par-3 and dynein co-assembly on recycling endosomes, lowers Notch signaling, and shifts divisions toward neuron–neuron outcomes at the expense of progenitors. Similar PCM1–PARD3–CEP83–RAB11 associations and asymmetr…

️ Episode 248: Disruption of PIKfyve triggers lysosomal repair and mitochondrial adaptation In this episode of PaperCast Base by Base, we explore Disruption of the PIKfyve/Fig4/Vac14 complex drives ULK1-dependent trafficking of PI4KIIα and ATG9A to lysosomes, elevating lysosomal PI(4)P to promote membrane repair and induce mitochondrial fragmentation with increased respiration Study Highlights:PIKfyve complex disruption or pharmacological inhibition reduces mTORC1 signaling, activating ULK1 and driving ATG9A-dependent trafficking of PI4KIIα from the TGN to lysosomes. PI4KIIα accumulation elevates lysosomal PI(4)P, recruiting OSBP/ORP proteins to transfer cholesterol and phosphatidylserine and enhance lysosomal membrane repair. Elevated lysosomal PI(4)P recruits ORP1L at ER–lysosome–mitochondria three-way contacts, enabling PI(4)P transfer to mitochondria, Drp1 recruitment, mitochondrial fragmentation, and increased oxygen consumption. Inhibition of ULK1 or PI4KIIα or mitochondrial tar…

️ Episode 247: Genome graphs reveal structural variation in M. tuberculosis In this episode of PaperCast Base by Base, we explore Long-read assemblies and a pangenome reference graph uncover widespre...

️ Episode 246: SV2A structural pharmacology and allosteric occlusion In this episode of PaperCast Base by Base, we explore High-resolution cryo-EM structures of human SV2A reveal that orthosteric ligands induce an occluded MFS conformation and a secondary allosteric pocket modulates ligand binding Study Highlights:The authors report sub-3 Å cryo-EM structures of human SV2A in the apo state and in complexes with levetiracetam, UCB-J, padsevonil, and the allosteric modulator UCB1244283. Levetiracetam and UCB-J bind the central cavity and drive inward movement of TM1 with Phe188 sealing the lumen, producing complete occlusion with levetiracetam and partial occlusion with UCB-J. UCB1244283 occupies a distinct allosteric site ~13 Å above the orthosteric pocket, reshapes the orthosteric site, lowers UCB-J Kd, increases Bmax, and slows ligand dissociation. Padsevonil binds both orthosteric and allosteric sites, precluding UCB1244283-mediated potentiation and illustrating overlapping but flex…

️ Episode 245: Benchmarking DNA foundation models In this episode of PaperCast Base by Base, we explore A comprehensive, unbiased benchmark compares five DNA foundation models across 57 datasets and multiple tasks, finding mean token embeddings improve classification and that model strengths vary by task and pre-training. Study Highlights:The study evaluated DNABERT-2, NT-v2, HyenaDNA, Caduceus-Ph, and GROVER on 57 datasets spanning sequence classification, gene expression prediction, variant effect quantification, and TAD recognition. Mean token embedding consistently and significantly outperformed summary-token and max pooling for sequence classification. Model performance was task-dependent: Caduceus-Ph excelled at human TFBS and promoter tasks, NT-v2 led pathogenic variant identification, HyenaDNA scaled efficiently and benefited from multi-species pre-training, while specialized models outperformed general foundations on QTL prediction. Zero-shot embeddings provided modest gene e…

️ Episode 244: NEK7 couples SDHB to preserve mitochondrial electron transport and limit liver fibrosis In this episode of PaperCast Base by Base, we explore Mitochondrial NEK7 is imported via MTS peptides, binds SDHB to stabilize complex II conformation, prevent reverse electron transport and ROS, and thereby protects against spontaneous and experimentally induced liver fibrosis Study Highlights:NEK7 localizes to hepatocyte mitochondria through two internal mitochondrial targeting signal peptides and co‑localizes with SDHB. NEK7 binds SDHB and stabilizes complex II spatial conformation without changing SDHB abundance or complex assembly. Hepatocyte NEK7 deficiency induces reverse electron transport, increases mitochondrial membrane potential and mtROS, suppresses respiration, and triggers spontaneous liver fibrosis while worsening CCl4‑induced fibrosis. RET inhibitors or NEK7 overexpression restore mitochondrial function and substantially attenuate CCl4‑ and CDAHFD‑induced liver fibro…

️ 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 pat…

️ 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 ra…

️ 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 avai…

️ 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…

️ 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 i…

️ 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…

️ 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 AT…

️ 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 HMT…

️ 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…

️ 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 pa…

️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 replica...

️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 o...

️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 ...

️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-...