Pineda PS et al., Nature Communications - 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. Key terms: cattle genomics, neocentromere, centromere evolution, telomere-to-telomere, structural variants.

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

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Article title:
Insights into natural neocentromere evolution from a cattle T2T X chromosome

First author:
Pineda PS

Journal:
Nature Communications

DOI:
10.1038/s41467-025-65778-w

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:
CC BY 4.0 International License

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/wagyu-t2t-x-neocentromere

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-27.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's core scientific claims as presented in the article, focusing on BTAX assembly, centromere architecture, epigenetics, neocentromere formation, gene content within BTAX, X-Y PAR, and improvements in SV discovery and mapping.
- transcript topics: BTAX assembly and haplotype-resolved X chromosome (UOA_Wagyu_1_Y); BTAX centromere structure: inverted repeats and TE content; absence of bovine satellites; Epigenetic features: CENP-A signal, methylation, CpG/TpG dynamics; Two-step model for neocentromere formation: TE expansion followed by CpG deamination; BTAX centromere gene content: 37 centromere genes, 24 newly identified; testes expression; Wagyu SV discovery and improved mapping rates using the Wagyu reference

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:
- BTAX centromere is a natural neocentromere located on the cattle X chromosome
- BTAX centromere consists primarily of highly identical inverted repeats and transposable elements
- BTAX centromere lacks bovine satellite repeats
- BTAX centromere exhibits low CENP-A signal and CpG depletion with low methylation relative to TpG dinucleotides
- Two-step model for neocentromere formation: TE expansion followed by CpG deamination
- BTAX contains 37 centromere genes; 24 of these are newly identified; all centromere genes are expressed in testes

QC result: Pass.

Ricci C et al., Nature Communications - Reduction of CYFIP1 delays callosal axon growth and arborization by lowering intracellular calcium and impairing mitochondrial function. Key terms: cyfip1, axon development, calcium, mitochondria, callosal connectivity.

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:
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Article title:
CYFIP1 governs the development of cortical axons by modulating calcium availability

First author:
Ricci C

Journal:
Nature Communications

DOI:
10.1038/s41467-025-65801-0

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

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/cyfip1-calcium-axon-development

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-26.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript segments covering in vivo axon development timing, calcium homeostasis, mitochondrial changes, CYFIP1-Hu interactions with CaV channel subunit mRNAs, and rescue experiments (ionomycin and VGCC agonists).
- transcript topics: CYFIP1 background and 15q11.2 CNVs; CYFIP1 dual roles: WRC actin regulation and translational repression; in vivo IUE and postnatal axon development timing (P5, P15, P30); mitochondrial density, motility, and morphology in Cyfip1+/- axons; intracellular Ca2+ dysregulation and mitochondrial function; CYFIP1 association with Hu proteins and regulation of CaV channel subunit mRNAs (CACNA1C, CACNA1E, CACNA1I)

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:
- CYFIP1 haploinsufficiency delays callosal axon growth and arborization in vivo with normalization by P30
- Cyfip1+/- cortical axons show reduced cytosolic/axo-plasmic Ca2+ and altered mitochondrial function (density, motility, membrane potential, ATP at early stages)
- CYFIP1 binds and stabilizes mRNA of CaV channel subunits CACNA1C, CACNA1E, CACNA1I via Hu proteins, affecting axonal calcium entry
- CaV channel subunits (CaV1.2 CACNA1C, CaV2.3 CACNA1E, CaV3.3 CACNA1I) are reduced in membrane fractions at DIV3 in Cyfip1+/- neurons; later stages show normalization
- mRNA levels of CACNA1E and CACNA1I are significantly reduced in Cyfip1+/- neurons; CACNA1C shows a non-significant downward trend
- Ionomycin and VGCC agonists Bay-K-8644 and Nefiracetam rescue delayed axonal growth and mitochondrial defects

QC result: Pass.

Genome Biology and Evolution - The Genomic Basis of the Svalbard Reindeer’s Adaptation to an Extreme Arctic Environment

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
The Genomic Basis of the Svalbard Reindeer’s Adaptation to an Extreme Arctic Environment

Journal:
Genome Biology and Evolution

DOI:
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

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-25.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing bottleneck/island colonization, PBS-based selection signals, SNPeff-derived variants, CNVs/structural variation, energy metabolism and fasting adaptations, circadian rhythm and vision adaptations, insulation/morphology (dwarfism), and discussed limitations/future directions.
- transcript topics: Population bottleneck and island colonization; PBS-based selection signals and outliers; SNPeff high- and moderate-impact variants; Copy number variation (CNV) and structural variation; Energy metabolism and fat storage; Leptin signaling and insulin resistance

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:
- Svalbard reindeer originated from a founder population likely fewer than 100 individuals around 7000 years ago.
- 62 reindeer genomes were sequenced, with populations from Svalbard, mainland Norway, mainland Russia, and Novaya Zemlya used for comparison.
- Population Branch Statistic (PBS) identified around 75 outlier regions under selection.
- SNPeff annotated variants yielded 1 high-impact and 54 moderate-impact variants within 44 genes.
- Copy number variation (CNV) analysis identified 124 differentiating CNVs; including 4 deletions and 10 duplications overlapping genes; large deletions (>500 bp) fixed in Svalbard.
- Overall, 150 genomic regions under putative selection were identified; ~120 of these correspond to annotated genes.

QC result: Pass.

Engelbrecht E et al., Nat Commun - 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. Key terms: immunoglobulin-kappa, immunoglobulin-lambda, germline-variation, antibody-repertoire, long-read-sequencing.

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:
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Article title:
Germline polymorphisms in the immunoglobulin kappa and lambda loci underpinning antibody light chain repertoire variability

First author:
Engelbrecht E

Journal:
Nat Commun

DOI:
10.1038/s41467-025-66759-9

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:
CC BY 4.0 International License

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/ig-light-chain-variation

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the core scientific narrative describing targeted SMRT sequencing of IGK/IGL loci, creation of personalized germline references, guQTL mapping linking variants to gene usage, variant mechanisms (coding, RSS, CNV), LD architecture differences, CDR3 physicochemical properties, and naive vs. antigen-experienced re
- transcript topics: IGK vs IGL locus architecture and diversity; SMRT long-read sequencing and personalized germline references; guQTL mapping and gene usage in IGK/IGL; Coding variants: IGKV2-29 stop codon; Coding variants: IGKV1-5 K50D; Regulatory variants: RSS spacers (IGLV3-16)

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:
- Long-read SMRT sequencing of IGK and IGL across 177 individuals with matched AIRR-seq (IGK n=164, IGL n=168).
- Personalized germline reference maps built for each individual to map expressed repertoires.
- >70% of light chain gene usage variation is explained by germline guQTLs in IGK/IGL.
- Lead variants include IGKV2-29 premature stop codon; IGKV1-5 K50D missense; RSS spacer variants in IGLV3-16; CNVs IGKV1-NL1, IGKV1-D-8, IGLV5-39.
- CDR3 aromaticity and aliphaticity are influenced by germline variants (guQTL-linked effects).
- IGK exhibits larger LD blocks and coordinated multi-gene usage; IGL shows smaller LD blocks and more independent usage.

QC result: Pass.

Thystrup C et al., Nat Commun (2025) - 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. Key terms: metagenomics, whole-genome sequencing, foodborne pathogens, one-health, surveillance.

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.

Article title:
Using metagenomics and whole-genome sequencing to characterize enteric pathogens across various sources in Africa

First author:
Thystrup C

Journal:
Nat Commun (2025)

DOI:
10.1038/s41467-025-66400-9

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:
CC BY 4.0 International License (CC 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/metagenomics-wgs-africa

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-23.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript’s discussion of study design (WGS vs metagenomics), multicountry sampling, major pathogen findings (E. coli, Salmonella, Campylobacter, Shigella), STs (ST131, ST38, ST1208), MAGs and their concordance with culture data, temporal sewage trends (2021), and limitations (database bias, AMR on plasmid
- transcript topics: WGS vs metagenomics methodological comparison; FOCAL project sampling across four African LMICs; Pathogen diversity across human, animal, food, and environmental reservoirs; E. coli typing (ST131, ST38) and Salmonella typing (ST1208); MAGs and culture-independent surveillance; Temporal trends in sewage pathogen burden (2021 spike)

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:
- 3,417 samples collected from 24 sources across four African LMICs (Ethiopia, Nigeria, Mozambique, Tanzania).
- 446 bacterial isolates recovered; 380 high-quality genomes subjected to downstream analyses.
- 168 metagenomic samples collected; 139 metagenomic samples passed quality control and were analyzed.
- 13 high-quality MAGs recovered (12 Escherichia coli and 1 Campylobacter).
- E. coli ST131 and ST38 detected across multiple countries/sources; Salmonella ST1208 identified as dominant lineage.
- Temporal sewage data show a notable increase in total FBD pathogen burden in 2021, temporally aligned with the COVID-19 pandemic.

QC result: Pass.

Paul T et al., Nat Commun - 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. Key terms: XPD, DinG, ssDNA translocation, nucleotide excision repair, disease mutations.

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:
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Article title:
Translocation mechanism of xeroderma pigmentosum group D protein on single-stranded DNA and genetic disease etiology

First author:
Paul T

Journal:
Nat Commun

DOI:
10.1038/s41467-025-66834-1

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

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/xpd-translocation-disease-etiology

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-22.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript portions describing XPD’s translocation mechanism, the seven-state ATPase cycle (S1–S7), the roles of Constriction 1 and Constriction 2, mutation class mapping to XP/CS/TTD phenotypes, XPD–DinG comparison, and per-nucleotide kinetic estimates.
- transcript topics: XPD function in nucleotide excision repair and lesion verification; XPD domain architecture and DNA-binding groove; Seven-state ATPase cycle (S1–S7) and translocation on ssDNA; Constriction 1 (5′ end) and Constriction 2 (3′ end) as molecular clamps; ATP binding/hydrolysis and mechanical coupling (spring spindle helix, Arch/Fe–S interactions); Disease mutations: XP, CS, TTD phenotypes and class mapping

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:
- XPD translocates 5′→3′ on ssDNA via a seven-state ATPase cycle (S1–S7).
- Two constrictions (Constriction 1 at the 5′ end and Constriction 2 at the 3′ end) act as molecular clamps enabling directional translocation.
- Mutations cluster at DNA-binding and ATPase sites and are categorized into three classes (A XP, B XP/CS, C XP/CS) with disease phenotypes XP, CS, and TTD.
- Key structural elements such as the spring helix and spindle helix couple motor-domain movements to Arch/Fe–S domains.
- XPD and DinG share a common architecture but differ in Fe–S domain anchoring; DinG lacks the XPD-specific anchoring element and shows different intermediate states (SD1–SD5).
- Per-nucleotide translocation times are predicted to be ~4 ms for XPD and ~9 ms for DinG; experimental rates on duplex DNA under load can be ~100 ms per nucleotide.

QC result: Pass.

Sands et al., Nature Communications - 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. Key terms: histone-methyltransferase, aRMAE, MET-2, SET-25, c-elegans.

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.

Article title:
Maternal histone methyltransferases antagonistically regulate autosomal random monoallelic expression (aRMAE) in C. elegans

First author:
Sands

Journal:
Nature Communications

DOI:
10.1038/s41467-025-66501-5

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:
CC BY 4.0 International License

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/maternal-h3k9-armae-c-elegans

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-21.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing MAE basics, the C. elegans reporter MAE assay, intrinsic noise as a MAE metric, the MET-2/SET-25 antagonism and cofactors, maternal deposition in the E-cell, catalytic SET-domain requirements, cross experiments, gene specificity, and translational implications.
- transcript topics: Introduction to autosomal random monoallelic expression (aRMAE); C. elegans MAE reporter system with dual-color alleles (hsp-90); Intrinsic noise as a quantitative MAE measure; RNAi screen identifying H3K9 methyltransferases MET-2 and SET-25; Antagonistic roles of MET-2 (negative regulator) and SET-25 (positive regulator) of MAE; Cofactors LIN-65, ARLE-14, HPL-2, LIN-61

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:
- Autosomal random monoallelic expression (aRMAE) is probabilistic, persistent within a tissue, but not heritable across generations.
- In C. elegans intestine, maternal MET-2 antagonizes SET-25 to regulate MAE; MET-2 promotes biallelic expression while SET-25 promotes monoallelic expression.
- Catalytic SET domains of MET-2 and SET-25 are required for their regulatory effects on MAE.
- Maternal MET-2 and SET-25 act in the E-cell of the 8-cell embryo to regulate MAE; the decision is propagated through somatic divisions but is not heritable.
- Cofactors LIN-65 and ARLE-14 support MET-2; HPL-2 and LIN-61 support SET-25 function.
- MAE regulation is gene-specific; not all MAE-prone genes respond similarly to MET-2 perturbation (e.g., hsp-90 vs vit-2).

QC result: Pass.

Petrova B et al., Proc Natl Acad Sci U S A - 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. Key terms: mthfr, one-carbon metabolism, methionine, metabolomics, long covid.

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.

Article title:
MTHFR allele and one-carbon metabolic profile predict severity of COVID-19

First author:
Petrova B

Journal:
Proc Natl Acad Sci U S A

DOI:
10.1073/pnas.2509118122

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:
CC BY 4.0 International License (CC 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/mthfr-methionine-covid-risk

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-20.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited substantive scientific content in the transcript: one-carbon metabolism and methionine cycle; MTHFR C677T polymorphism; IMPACC cohort design with visit-1 sampling within 72 hours; early metabolite perturbations (methionine, methionine sulfoxide, SAH, glycine, serine); two-hit hypothesis; predictive modeling (AI
- transcript topics: One-carbon metabolism and the methionine cycle; MTHFR C677T polymorphism and AA homozygosity; IMPACC cohort design and visit-1 sampling within 72 hours; Early metabolite changes: methionine, methionine sulfoxide, SAH, glycine, serine; Long COVID risk and trajectory analyses; Two-hit hypothesis and predictive modeling (AIC)

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:
- Combined MTHFR AA genotype with acute methionine-cycle metabolite levels (SAH, methionine, methionine sulfoxide) improves prediction of mortality and long COVID risk
- Visit 1 samples were collected within 72 hours of hospital admission
- SAH and methionine sulfoxide levels are elevated with higher disease severity; glycine and serine changes observed in relation to severity
- MTHFR C677T AA allele frequency in IMPACC is 13.3% (AA allele), with ~10–15% globally for the AA variant
- AIC-based model comparison shows substantial improvement when adding MTHFR genotype and methionine-cycle metabolites to clinical data (AIC ~790.85 -> ~738.66; χ2(3)=58.2, P<0.001)
- Long COVID risk is predicted by combining MTHFR allele status with early one-carbon metabolite changes

QC result: Pass.

Shi W et al., Mechanistic insights into histone recognition and H3K14 acetylation by the NuA3 histone acetyltransferase complex - Cryo-EM structures of the yeast NuA3 complex show a composite histone tail binding cleft formed by Sas3 and Nto1 that dictates selective acetylation of H3K14. Key terms: NuA3, Sas3, Nto1, H3K14 acetylation, cryo-EM.

Study Highlights:
The six-subunit NuA3 complex was purified and shown to acetylate H3K14 preferentially on H3K4- or H3K36-trimethylated substrates. Cryo-EM maps of the apo, acetyl-CoA-bound, and acetyl-CoA plus H3 tail-bound states were determined at 3.7 Å, 3.1 Å, and 3.2 Å resolution, respectively. The H3 tail binding cleft is formed cooperatively by the catalytic Sas3 MYST domain and the Nto1 PZP region, with a hydrophobic pocket engaging H3 residues 9–12 and a network of polar contacts around Gly13–Ala15 that confer site specificity. Mutations predicted to disrupt contacts (L369R, N354A, E452Q) impair or abolish HAT activity in vitro and reduce H3K14 acetylation in yeast. Binding of acetyl-CoA induces conformational shifts in a histone-engaging loop and a CoA-engaging helix that likely position catalytic residues for transfer

Conclusion:
The structures define how cooperative recognition by Sas3 and Nto1 and local conformational changes confer high specificity for H3K14 acetylation and suggest conservation of this recognition mode in human homologs

Music:
Enjoy the music based on this article at the end of the episode.

First author:
Shi W

Journal:
Mechanistic insights into histone recognition and H3K14 acetylation by the NuA3 histone acetyltransferase complex

DOI:
10.1038/s41467-025-67049-0

Reference:
Shi W., Zhao L., Wang Y., Zhang Y., Liu S., Wang Y., Kornberg R. D., Zhang H. 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

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/nua3-h3k14-structure

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-19.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's coverage of NuA3 structure-function findings: complex composition, cooperative histone tail binding cleft, acetyl-CoA–induced conformational priming, substrate specificity with Gly13, mutational evidence (L369R, N354A, E452Q), recruitment marks (H3K4me3/H3K36me3), and cross-species conservation
- transcript topics: NuA3 subunit composition; Cooperative H3 tail binding cleft formed by Sas3 and Nto1; Acetyl-CoA binding and conformational priming; Substrate specificity and Gly13 determinant; Mutational effects: L369R, N354A, E452Q; Recruitment marks: H3K4me3 and H3K36me3

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:
- NuA3 is a six-subunit histone acetyltransferase complex (Sas3, Nto1, Yng1, Eaf6, Taf14, Pdp3).
- NuA3 acetylates histone H3K14 and recruitment depends on pre-existing marks H3K4me3 and H3K36me3.
- A deep histone tail binding cleft is formed cooperatively by Sas3 and Nto1, yielding site specificity for H3K14.
- Acetyl-CoA binding to Sas3 primes the complex by repositioning the histone-engaging loop and the CoA-engaging helix to facilitate tail docking.
- Gly13 preceding K14 acts as a critical determinant; G13R mutation reduces or abolishes HAT activity.
- Mutations L369R and N354A disrupt histone-tail interactions; E452Q abolishes catalytic activity.

QC result: Pass.

Cherdyntseva V et al., Nat Commun - 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. Key terms: Lamin A/C, replication fork, H3K9me3, PARylation, RECQ1.

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.

Article title:
Nucleoplasmic Lamin A/C controls replication fork restart upon stress by modulating local H3K9me3 and ADP-ribosylation levels

First author:
Cherdyntseva V

Journal:
Nat Commun

DOI:
10.1038/s41467-025-66098-9

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:
CC BY 4.0 / Creative Commons Attribution 4.0 International License

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/nucleoplasmic-lamin-fork-restart

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-18.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript’s substantive coverage of the Lamin A/C–H3K9me3–PAR axis controlling fork slowdown and RECQ1 restart under mild replication stress, including roles of LAP2α, G9a, KDM3A, and ChromStretch mapping.
- transcript topics: Lamin A/C dynamic interaction with replication factories; Acute Lamin A/C depletion and LAP2α effect on fork slowing; RECQ1-mediated fork restart and genetic rescue by RECQ1 depletion; Local PARylation at replication forks and Lamin A/C control; H3K9me3 accumulation at forks and maintenance by Lamin A/C via KDM3A; G9a-driven chromatin methylation and chromatin compaction

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:
- Lamin A/C dynamically interacts with replication factories throughout the nucleus
- Acute Lamin A/C depletion abolishes active fork slowing under mild replication stress; LAP2α depletion yields a similar phenotype
- RECQ1 restart contributes to fork restart; RECQ1 depletion rescues slowed forks
- PARylation levels at replication forks are locally reduced after Lamin A/C loss and can be restored by PARG inhibition
- H3K9me3 accumulates at replication forks under mild replication stress and Lamin A/C maintains this mark by inhibiting the demethylase JMJD1A/KDM3A
- G9a inhibition phenocopies Lamin A/C loss, reducing PAR at forks and deregulating RECQ1 restart; PARG inhibition can rescue

QC result: Pass.