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Oct 14Wed
  1. Mol Cell65

    A feedback mechanism of m6A via PARP1-mediated ADP ribosylation of METTL3/METTL14.

    The m6A reader IGF2BPs recruits PARP1 to m6A-modified RNAs and stimulates its activity, leading to ADP ribosylation of the m6A writer METTL3/METTL14, which impairs its RNA-binding capability and reduces m6A deposition in human cell lines. This "read-orchestrate-write" negative feedback loop expands the regulatory paradigm of m6A methylation beyond the writer/eraser/reader system. Combining PARP inhibitor therapy with inhibition of IGF2BP2 or METTL3 produced synergistic anti-tumor effects.

  2. biorxiv.org50

    Biomarker-driven and gene-enhanced viral therapy for malignant peripheral nerve sheath tumor

    Loss of the PRC2 histone mark H3K27me3, common in high-grade MPNST, sensitizes tumors to the oncolytic HSV G47Δ, but also triggers a compensatory integrated stress response that blunts viral protein translation. Engineers built G47Δ² with tumor-regulated ICP34.5 expression (BIRC5-driven), limiting daily xenograft tumor-volume growth to 0.6% (95% CI -2.9–4.2%) versus 8.3% for G47Δ² and 22.5% for controls, though murine gastrointestinal toxicity reduced event-free survival.

Oct 13Tue
  1. medrxiv.org48

    Methylation-defined tumour subgroups guide recognition of genetic predisposition in Wilms tumour

    DNA methylation profiling of 138 Wilms tumours identified five molecular clusters that capture predisposition-associated heterogeneity, including a distinct WT1-driven subgroup. Cluster-guided reanalysis uncovered previously unrecognised WT1 pathogenic variants, one of which led to surveillance enrolment, and a random forest classifier predicted WT1-driven tumours with ~90% accuracy in independent validation cohorts. Tumour methylation profiling can thus guide targeted variant reanalysis and reveal germline variants missed by standard diagnostics.

    Why it matters: Because it shows tumour methylation can flag germline predisposition that standard diagnostic workflows miss.

Oct 12Mon
  1. Sci Adv64

    SMCHD1 is a target for gene activation therapy to treat Prader-Willi syndrome.

    SMCHD1 represses the entire Prader-Willi syndrome locus in neural lineages in both mice and humans, making it a candidate target for activating the silenced maternal copy of the disease genes. Deleting Smchd1 after early development in vivo activated PWS genes in disease-relevant mouse tissues including hypothalamus and improved phenotypes in a PWS mouse model. Genome-wide SMCHD1 binding aside, this postearly targeting appeared safe, supporting gene activation therapy for the underlying cause of PWS rather than individual symptoms.

    Why it matters: It identifies a molecular target that activates the silenced maternal allele and improves disease phenotypes in a PWS mouse model.

Oct 11Sun
  1. biorxiv.org65

    Structural variants from donor-specific assemblies affect recurrent chromatin contact divergence in humans

    Donor-specific genome assemblies markedly improve mapping of haplotype-resolved chromatin contacts: across 354 human and 12 nonhuman ape haplotypes, 13.2% of cis Hi-C contacts showed >25 kbp changes in inferred genomic separation and 2.8% more valid contact pairs were recovered compared with standard references. Haplotype-specific chromatin differences are selective, concentrating in 1,790 recurrent contact difference hotspots linked to 2,495 chromatin-structure-associated structural variants enriched in regulatory contexts and associated with expression variation; over 90% of these SVs arose in the human lineage. The work argues for building pangenome haplotype diversity into studies of 3D genome organization.

    Why it matters: Quantifies how much standard references distort chromatin contact maps and pinpoints specific structural variants behind recurrent haplotype differences.

  2. biorxiv.org52

    Transcriptional perturbation effects remain structured beyond the leading global trend

    Gene perturbations contribute unevenly to the known leading global transcriptional trend, and substantial structure persists beyond it, including perturbation-specific effects that transfer across datasets and a common hierarchy of responsive genes shared across perturbations. These patterns let simple prediction strategies stay competitive even for effects beyond the leading global component.

  3. biorxiv.org62

    Spatiotemporal AI modeling of gene regulation and variant effects in the developing human brain

    Seal, an interpretable AI transfer learning framework, models gene expression and variant effects with spatiotemporal resolution across 26 brain regions, 30 cell types, and seven developmental stages of the human brain. Applied to GWAS, it identifies cell types and developmental windows relevant to six neuropsychiatric conditions, and in Simons Simplex Collection autism whole genome data it uncovers a significant burden of de novo regulatory variants in transient fetal excitatory neurons.

    Why it matters: It links disease-associated variants to specific cell types and developmental windows in the developing brain.

  4. biorxiv.org69

    Scalable methylome-transcriptome profiling resolves clonal organization in human hematopoiesis

    Droplet-MT jointly profiles transcriptomes and methylomes at ~10,000 cells per library, using methylation epimutations for mutation-independent clonal reconstruction and label transfer at ~0.2% CpG coverage to cut sequencing cost. Applied to ~21,000 paired profiles from healthy blood and longitudinal acute myeloid leukemia, it resolved small and expanded clones with heterogeneous lineage output and distinguished malignant clonal abundance changes, state remodeling within persistent clones, and recovery of healthy polyclonal hematopoiesis. Malignant monocytes stayed transcriptionally and epigenetically distinct from healthy and recovery-associated cells despite treatment-associated remodeling.

    Why it matters: It offers a scalable way to link clonal ancestry to molecular state in human hematopoiesis and leukemia.

Oct 10Sat
  1. Cell83

    A fluctuation test for gastruloid heterogeneity.

    Organoid heterogeneity traces partly to heritable differences in founder stem cells, not just culture conditions. Monoclonal gastruloids grown from single mouse embryonic stem cells showed extensive variability in development, mesodermal versus neural bias, and atypical cell types. DNA Typewriter lineage recording showed that fate biases arise before gastruloid induction, with more closely related founders producing more phenotypically similar gastruloids, and that fate-predictive differences map to gene expression, chromatin accessibility and imprinted loci.

    Why it matters: It locates a cell-intrinsic, heritable source of organoid heterogeneity and provides a lineage recorder to track it.

  2. Science79

    Epigenetic aging and transposon dysregulation reflect size-related lifespan compression in dogs.

    An epigenetic clock built from 1640 methylomes of 894 dogs predicted mortality and showed that epigenetic aging is fastest early in life. Larger and male dogs, which are shorter lived, showed accelerated molecular aging through distinct architectures: sex-dependent methylation concentrated on the X chromosome and size-associated methylation pronounced at transposable elements. The work identifies transposable elements as potential mediators of size-associated lifespan.

    Why it matters: Links body size to lifespan via transposable element methylation in a natural mammalian aging model.

  3. biorxiv.org57

    Multi-omic long-read sequencing reveals nucleosome control of transcriptional fidelity at the isoform level

    Nucleosome organization controls transcriptional fidelity from initiation through splicing, according to long-read single-molecule profiling in yeast. Deleting the chromatin remodelers ISW1 and CHD1 in Saccharomyces cerevisiae and sequencing chromatin fibers, nascent RNA and full-length mature RNA with Oxford Nanopore reads showed that single-molecule chromatin states plus sequence motifs strongly predict alternative TSS isoform expression, and that loss of the remodelers activated silenced promoters while repressing active ones. Disrupted nucleosome spacing also impaired RNAPII processivity and co-transcriptional splicing, changing mature RNA levels and splicing isoform composition.

Oct 9Fri
  1. doi.org70

    SETDB1 preferentially silences evolutionarily young retroelements

    SETDB1 silences a restricted, locus-specific subset of LTR retroelements rather than all transposable elements, according to long-read RNA sequencing in a telomere-to-telomere mouse genome assembly. Time-resolved SETDB1 depletion with ChIP-seq showed ERVK and ERV1 elements lose H3K9 methylation and gain Pol II, while LINE/L1 elements activate transcription without H3K9me3 loss, implicating parallel repressive mechanisms for LINEs. The work refines models of heterochromatin-mediated transposable element control.

    Why it matters: Resolves locus-specific SETDB1 targets previously obscured by short-read mapping, separating direct from parallel silencing mechanisms.

  2. biorxiv.org40

    Coordinated alterations in SWI/SNF chromatin remodeling complex, mRNA splicing and mRNA methylation as hallmarks of salivary gland adenoid cystic carcinoma (SACC)

    Spatial transcriptomics of salivary gland adenoid cystic carcinoma points to coordinated disruption of epigenetic regulation as a contributor to the disease. The SWI/SNF chromatin remodeling complex, the NineTeen Complex, and the m6A RNA methylation complex were shown to interact directly, and immunohistochemistry on 48 tumor samples showed altered abundance of METTL3, METTL14, WTAP, PRP19, CDC5L and PLRG1 proteins. BRM directly regulates genes encoding subunits of these complexes and some EMT marker genes, and re-analysis revealed broad alterations in transcript usage and splicing events.

Oct 8Thu
  1. biorxiv.org47

    Heterochromatin protein 1α acts as an essential stabilizer of chromatin packing domains

    Degrading heterochromatin protein 1 alpha (HP1α) unexpectedly caused overall gene downregulation rather than increased transcription, contradicting the canonical view of heterochromatin as purely repressive. Heterochromatic cores of dense chromatin packing domains were disrupted, though some domains persisted, and under hypoxia HP1α-depleted cells showed a dampened transcriptional response. The findings position HP1α crosslinking as essential for packing domain maturation and efficient transcriptional reprogramming.

  2. biorxiv.org45

    Sex-dependent DNA methylation in amyotrophic lateral sclerosis

    A blood-based epigenome-wide association meta-analysis of 8,946 individuals (5,129 males, 3,817 females) from Project MinE and an Australian cohort identified seven sex-dependent ALS-associated differentially methylated positions at P < 9 × 10-8, mapping to KCNQ1, ADPRH, HLA-F, GHRLOS, IRF5, RAD51B and one intergenic region. Sex-stratified case-control analyses alone found no genome-wide significant sex differences; the interaction model did, with the strongest signal at KCNQ1 (P = 3.1 × 10-9). Six of the seven positions survived a four-stratum sensitivity analysis and none appeared in previous conventional ALS methylation analyses, pointing to a distinct sex-conditional component of the ALS blood methylome.

  3. Sci Adv45

    Epigenetic insights into extreme longevity in the world's oldest terrestrial animal, Jonathan.

    Whole-genome and methylome sequencing of Jonathan, a 194-year-old Aldabra giant tortoise, revealed unique gene variants in most aging pathways relative to other giant tortoises, plus pronounced DNA methylation and methylation entropy changes compared with four other Aldabras aged from a 5-year-old juvenile to older adults. Low-entropy regions were enriched for promoters of mitochondrial electron transport chain and RNA metabolism genes, suggesting high-fidelity transcription in these pathways supports longevity.

Oct 7Wed
  1. nature.com81

    tRNA dosage regulates lineage dependency and resistance in prostate cancer

    A single tRNA species, tRNA1Arg(UCU), is downregulated during prostate cancer lineage plasticity and acts as a key regulator of lineage conversion and therapy resistance. In LNCaP models of the adenocarcinoma-to-lineage-plastic transition, tRNAArg(UCU) was the only significantly downregulated isoacceptor among 49 (DESeq2 log2FC = -0.338, FDR = 2.42 x 10-25). Restoring it sensitizes tumours to AR pathway inhibitors, its dosage controls lineage dependency through translational regulation of SMARCC2, and its loss marks NE prostate cancer and reduced overall survival.

    Why it matters: Links a specific tRNA to lineage plasticity and ARPI resistance in prostate cancer, with a druggable restoration effect.

  2. biorxiv.org40

    Combined HDAC and ATM inhibition with radiation in preclinical glioblastoma models

    The HDAC inhibitor quisinostat and the ATM inhibitor AZD1390 produced synergistic radiosensitization in patient-derived glioma stem cells in vitro, with quisinostat increasing histone acetylation and suppressing homologous recombination gene transcription while AZD1390 blocked ATM signaling. In an orthotopic glioblastoma model, quisinostat plus radiation significantly prolonged survival over radiation alone, but adding AZD1390 conferred no additional benefit. The finding narrows the promising radiosensitizing combination to HDAC inhibition plus radiation.

  3. Cancer Cell69

    Chromatin accessibility trajectories reveal pre-cancerous epigenetic priming and an acid-driven immunotherapy-resistant gastric cancer subtype.

    A chromatin accessibility atlas of 650 multistage samples from 439 patients traces epigenetic switches across stepwise gastric tumorigenesis, showing that intestinal metaplasia carries a cancer-resembling priming state that licenses tumor initiation. Advanced tumors split into three epigenomic subtypes: proliferative and mesenchymal-inflammatory subtypes respond to neoadjuvant immunotherapy, while the pseudo-gastric subtype is intrinsically drug resistant. FOSL2-driven up-regulation of H+/K+ ATPase transporters sculpts an acidic milieu suppressing CD8+ T cells, and FOSL2 depletion or the acid blocker vonoprazan sensitizes immunotherapy.

    Why it matters: It defines an acid-driven immunotherapy-resistant gastric cancer subtype and a clinically available drug, vonoprazan, that reverses it.

  4. biorxiv.org51

    Adenosylhomocysteinase drives epigenetic and metabolic reprogramming in ZFTA-RELA ependymoma

    ZFTA-RELA-positive supratentorial ependymomas depend on AHCY, which the fusion upregulates to raise methylation potential, activating CAD via H3K4me3 and repressing ASNS via H3K27me3, shunting aspartate into pyrimidine biosynthesis while creating extracellular asparagine dependency through SLC1A5 stabilization. Inhibiting AHCY genetically or pharmacologically, restricting S-adenosylmethionine, or blocking EZH2 reversed these epigenetic states and suppressed tumor growth in vitro and in vivo.

  5. biorxiv.org47

    Disconnect Between Succinate, Succinyl-CoA, and Histone Succinylation in Cells and Gastrointestinal Stromal Tumors with Succinate Dehydrogenase Deficiency

    Succinate dehydrogenase (SDH) deficiency raises succinyl-CoA in multiple models, but histone succinylation does not increase, and lysine malonylation and glutarylation instead decrease. Liquid chromatography high resolution mass spectrometry across the NCI-60 panel, SDH-deficient and SDH-competent models, and GIST patient tumors showed no correlation between succinate to fumarate ratio and succinyl-CoA, and no rise in succinyl-CoA or desuccinylase expression in bulk tumors. Pharmacological desuccinylase inhibition showed very weak or no selective effect on SDH-deficient cell viability, challenging proposed succinylation-based therapeutic targeting.

  6. biorxiv.org58

    Loss of the Y chromosome drives basal identity and metastatic potential via epigenetic reprogramming in pancreatic cancer

    Loss of the Y chromosome (LOY) affects ~50% of male pancreatic ductal adenocarcinoma patients across two independent cohorts, with enrichment in advanced disease and the basal subtype. Y-chromosome deletion alone in CRISPR-engineered PDAC models induces EMT transcriptional states, mesenchymal morphology and enhanced metastatic ability, via loss of Y-linked chromatin modifiers that reshape DNA methylation at EMT- and basal-defining loci. The work establishes LOY as a causal driver of PDAC progression and a clinically accessible biomarker.

Oct 6Tue
  1. Mol Cell67

    An epigenetic program dictates MYC amplification dynamics that promote transient, extrachromosomal, and inherited genomic events.

    H3K4 methylation primes MYC for amplification by the H3K9/K36 tri-demethylase KDM4C, while the H3K36 tri-methyltransferase SETD2 restrains copy gains. SETD2 loss or inhibition promotes recruitment of catalytically active KDM4C, which initiates stepwise MYC copy gains; suppressing apoptosis or losing TP53 accelerates higher-level amplification, including eccDNAs and inherited copy gains that render non-transformed cells tumorigenic. KDM4C inhibition suppresses MYC amplification, defining a chromatin-apoptotic axis and a potential therapeutic target.

    Why it matters: Defines an epigenetic and apoptotic mechanism driving MYC amplification from diploid genomes, with KDM4C as a druggable target.

  2. biorxiv.org46

    Disease-associated mutations directionally modulate epigenetic age in iPSC-derived tissues

    Epigenetic age progressively increases with serial passaging of iPSC-derived lung organoids (alveolospheres), measured by multiple epigenetic clock models, providing a reproducible in-vitro way to re-establish aging trajectories lost at reprogramming. Disease-associated mutations added cell-intrinsic shifts in epigenetic age across multiple models, marking disease state as an independent modulator of epigenetic clocks. The work extends iPSC systems to modeling age-associated cellular states beyond genetics.

  3. biorxiv.org49

    Distinct sequence grammars of nucleosomal and linker DNA shape mutational and methylation landscapes in cancer

    DeepND, an interpretable deep learning framework, distinguishes nucleosomal from inter-nucleosomal DNA and identifies 210 sequence motifs of 2-16 bp length that are significantly enriched or depleted in nucleosomal DNA. Forty-four of these motifs show cancer-type-specific enrichment or depletion of somatic mutations, and six are associated with differential DNA methylation levels. In lung and endometrial cancers, mutations show a significant ~10-bp periodic enrichment pattern across distinct minor-groove orientations, linking mutational and repair processes to nucleosome rotational positioning.

Oct 5Mon
  1. Nature72

    Type 2 immune history trains lung macrophages for viral disease tolerance.

    Prior type 2 inflammation from Nippostrongylus brasiliensis infection made mice fully survive lethal H1N1 influenza challenge 4-6 weeks later, while all unconditioned controls died by days 5-6. Protection came through reduced immunopathology, increased efferocytosis and accelerated tissue repair rather than lower viral burden, and required nerve- and airway-associated macrophages (NAMs) bearing an IL-4-STAT6-PPARγ and ARG1 chromatin program. The work establishes local trained immunity in lung-resident macrophages as a mechanism of viral disease tolerance.

    Why it matters: Identifies a macrophage-based trained-immunity mechanism for disease tolerance that could be targeted in severe respiratory viral infections.

  2. Sci Adv63

    Aging-associated SATB1 deficiency remodels 3D genome architecture and transcriptional programs in naive CD4+ T cells.

    Aging remodels 3D genome architecture in murine naive CD4+ T cells, weakening topologically associating domain boundaries and rewiring enhancer-promoter contacts while up-regulating inflammatory and T cell activation genes. These structural changes partly trace to declining expression of the chromatin organizer SATB1, which normally constrains CTCF-mediated interactions; conditional SATB1 deletion in naive T cells recapitulates the aging-associated genomic and transcriptional changes.

    Why it matters: It links immune aging to a specific structural mechanism, SATB1 loss, that can be reproduced by deletion in naive T cells.

Oct 3Sat
  1. Nature79

    Histone readers MLLT1 and MLLT3 concentrate AID to confer locus specificity.

    The super elongation complex histone readers MLLT1 and MLLT3 prove to be determinants of selective AID activity in antibody diversification. Combined loss of the two readers abolishes all AID-dependent mutagenic processes, recapitulating AID deficiency, while transcriptional changes after deletion are modest. The readers locally enrich AID downstream from promoters, with MLLT1 acting dominantly in mice through condensate formation, and fusing AID to either reader restores class-switch recombination and mutagenesis in double-knockout cells.

    Why it matters: Identifies the histone readers that confer locus specificity to AID, explaining off-target mutagenesis in B cell lymphoma.

Oct 2Fri
  1. biorxiv.org62

    Topoisomerase-mediated resolution of negative DNA supercoiling sustains human transcription and gene activation

    Topoisomerase-mediated resolution of negative DNA supercoiling is required for productive transcription in human cells. Acute topoisomerase perturbation lets negative supercoiling accumulate around transcription start sites, slows RNAPII elongation, increases promoter-proximal pausing, and, upon TOP1 depletion, raises gene expression noise by cutting transcriptional burst size and frequency while weakening enhancer-promoter loops. During T-cell activation, impaired supercoiling resolution compromises rapid gene upregulation.

  2. Nature79

    Population-scale immune multiome atlas reveals regulatory disease mechanisms.

    Simultaneous single-nucleus profiling of chromatin accessibility and gene expression in 10 million peripheral blood mononuclear cells from 1,108 Finnish individuals yields 51,083 cis-expression QTLs, 338,100 cis-chromatin accessibility QTLs and 593,765 peak-gene links. Variants completing chromatin-to-expression cascades show twice the disease colocalization of chromatin-only effects, and massively parallel reporter assays validate 10,428 fine-mapped QTLs. The atlas supplies testable hypotheses for over half of immune disease associations and explains why disease variants preferentially target evolutionarily constrained genes through regulatory buffering at the chromatin-to-expression interface.

    Why it matters: It converts non-coding immune disease variants into mechanistic chromatin-to-expression cascades for most immune disease associations.

  3. Cell68

    Condensates of the chromatin regulator ANKRD11 restrict hypertranscribed genes to safeguard development.

    The chromatin regulator ANKRD11 forms biomolecular condensates, via charge-block-patterned intrinsically disordered regions, that sequester elongation factors away from RNA polymerase II and restrict transcription of highly transcribed genes. A two-tiered genetic screen identified a network of such regulators enriched for developmental disorder genes. Ankrd11 loss in mice caused aberrant developmental gene activation, disrupted organogenesis and embryonic lethality, and KBG patient cells showed defective condensate formation with overactivation of hypertranscribed genes.

  4. Cell67

    Robust regulatory interplay of enhancers, facilitators, and promoters in a native chromatin context.

    A recombinase-mediated genome-rewriting platform dissected how the human enhancer eNMU activates its target gene Neuromedin U (NMU) by 10,000-fold at the native locus. The enhancer splits into the autonomous element e1 and an inactive facilitator e2 that augments e1, with e1 hierarchically dominant over facilitators and the NMU promoter across the ~100-kb region and organizing a 3D regulatory hub. e1 itself contains an LTR enhancer plus an adjacent LTR promoter that dampens NMU expression.

  5. Nature70

    Transcription pause and elongation regulators mediate somatic hypermutation.

    Somatic hypermutation requires the transcription pause regulator NELF plus the super elongation complex components MLLT1 and MLLT3 and the INT-PP2A phosphatase module. NELF associates with RNA polymerase II in the AID target window, and without NELF, AID still reaches chromatin and PolII still transcribes, but cytosine deamination fails. MLLT1 and MLLT3 bind AID through their YEATS domain and are needed to enrich AID at its target sites, assigning NELF-PolII pausing in gene bodies a role in generating the AID substrate.

    Why it matters: It identifies the pause and elongation factors that generate the substrate AID acts on during antibody affinity maturation.

  6. biorxiv.org45

    Genetic risk and inflammatory signaling converge on cell type-specific regulatory programs in type 1 diabetes

    A subset of type 1 diabetes-associated variants may drive beta-cell dysfunction by disrupting transcription factor binding at cell type-specific candidate cis-regulatory elements. The authors integrated epigenomic and single-cell multiomic data from human pancreatic islets with T1D GWAS variants, and used the deep learning model ChromBPNet plus TF footprinting to nominate several disease-associated SNPs predicted to alter chromatin accessibility at candidate TF binding sites. The work links noncoding variants to cell type-specific enhancer activity and provides candidates for future mechanistic studies.

  7. biorxiv.org46

    A ncBAF to cBAF Switch Regulates Human Hematopoietic Progenitor Myeloid Differentiation

    Loss of the ncBAF subunit BRD9 in adult human hematopoietic stem and progenitor cells displaces ncBAF from chromatin and enhances cBAF recruitment to CEBPA target sites, skewing differentiation toward myeloid-derived suppressor cells that secrete elevated IL-8. Soluble factors from BRD9-deficient myeloid cells increased stemness of breast cancer cells in vitro. Bromodomain inhibition of BRD9, unlike degradation, minimally altered ncBAF binding and myeloid differentiation, showing BRD9 blocks MDSC differentiation independently of its bromodomain.

Oct 1Thu
  1. biorxiv.org58

    Tumor suppressor-like mutations mark a dosage-constrained dependency in leukemia

    Recurrent heterozygous loss-of-function mutations in the transcription factor EBF3, a classic tumor suppressor signature, actually mark a gene essential for acute promyelocytic leukemia survival. PML::RARA drives EBF3 expression through a p300-dependent intronic enhancer, but excess EBF3 suppresses proliferation, so patient mutations calibrate EBF3 within a fitness corridor. p300 inhibition pushes EBF3 below the viability threshold, exploiting this dependency. The finding shows oncogenes can impose dosage constraints that produce mutations misread as tumor suppressor loss.

  2. nature.com61

    A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation

    Proteomic and phosphoproteomic analyses of lysosomes uncovered a TBK1/ULK1 signalling axis that activates TFEB in response to lysosomal stress, independent of nutrient-sensing by mTORC1. This regulatory arm mediates lysosomal adaptation to stress, and its deregulation was linked to tumorigenesis in follicular lymphoma. The work adds a nutrient-independent branch to the mTORC1 signalling framework at the lysosome.

    Why it matters: Identifies a new lysosomal stress signalling pathway and connects it to follicular lymphoma tumorigenesis.

  3. nature.com74

    Histone readers MLLT1 and MLLT3 concentrate AID to confer locus specificity

    The paper reports that the histone readers MLLT1 and MLLT3 concentrate AID to confer locus specificity. Analyses included ChIP-seq, TT-seq, Nanopore amplicon-seq and BioID proteomics in B cell lines such as CH12F3 and Ramos, together with reanalysis of public datasets on histone acetylation, AID occupancy and aberrant somatic hypermutation in B cell lymphoma. Data and custom analysis code were deposited in public repositories.

    Why it matters: It identifies MLLT1 and MLLT3 as factors that concentrate AID and determine its genomic targets.

Sep 30Wed
  1. biorxiv.org70

    RNA splicing factor mutations drive myeloid neoplasm oncogenesis through protein complex poisoning

    Splicing factor mutations in myeloid neoplasms poison entire functional protein complexes, not just individual transcripts. Single-cell transcriptomics (10X-ONT, n = 21) and immunophenotype-resolved pauciproteomics (n = 78) across 62 patients and 20 healthy donors show that mutation-specific RNA mis-splicing decouples protein from transcript dynamics during hematopoietic differentiation, effects invisible to transcriptomics alone and validated in iPSC differentiation models.

    Why it matters: Protein-level consequences of splicing factor mutations are invisible to transcriptomics, changing how these oncogenic events should be studied.

Sep 29Tue
  1. biorxiv.org58

    Epigenetic progression of pancreatic cancer to aggressive subtypes involves alternate routes of lineage reprogramming in subtype-intermediate progenitor cells

    Single-cell ATAC-seq of 33 primary tumors and 7 metastases from 39 PDAC patients, paired with 10 single-cell RNA-seq profiles, maps the cis-regulatory landscape underlying malignant cell state plasticity. GATA6+/KRT17+ co-accessibility marks a classical-basal subtype-intermediate progenitor state (SIP) with limited epigenetic reprogramming and better clinical outcomes. Classical tumors repressing basal accessibility activate neural-like progenitor and tuft lineage enhancers, while basal committed tumors show esophageal transdifferentiation, both with poorer outcomes and distinct immune and stromal phenotypes.

    Why it matters: Defines epigenetic lineage routes and a progenitor state that stratify PDAC outcomes and tumor microenvironment phenotypes.

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