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#染色质/3D基因组

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Oct 15Thu
  1. biorxiv.org58

    Dissection of Polycomb complexes reveals canonical PRC1-independent 3D chromatin interactions

    Polycomb-mediated 3D chromatin interactions persist even when canonical Polycomb repressive complex 1 (cPRC1) is depleted, contradicting existing models that place cPRC1 at the center of this process. Using Polycomb subunit degrons combined with Region Capture Micro-C, ChIP-seq, nascent transcriptomics, and live-cell imaging, the authors show that within cPRC1, polyhomeotic proteins are the main contributors to interactions, and that the residual interactions do not depend on any single variant PRC1 or PRC2 complex. The work raises the possibility of a more general, cPRC1-independent mechanism for Polycomb-mediated interactions.

Oct 14Wed
  1. Cell80

    Rare k-mers reveal centromere haplogroups underlying human diversity and cancer translocations.

    Rare k-mers in centromeric regions define discrete haplogroups with distinct structural features, which the new tool ascairn infers from short-read WGS. Across >3,300 genomes, centromere haplogroups show extensive global diversity and signatures of population history. In 142 oligodendroglioma cases with 1p/19q co-deletion, breakpoints in chromosomes 1 and 19 map to kinetochore attachment sites, linking centromere haplotype structure to rearrangement susceptibility.

    Why it matters: It makes centromeres analyzable at population scale and ties their structure to cancer translocations.

  2. Cell74

    Mechanisms of transcription control by distal enhancers from single-gene nanoscopy.

    Real-time single-gene nanoscopy with targeted perturbations shows that productive enhancer-promoter interactions are dynamic, occur within roughly 100 nm, and are coordinated with transcriptional bursts. Enhancers and promoters are often actively brought together by cohesin-mediated loop extrusion, a key determinant of burst frequency, and enhancers activate bursting by embedding promoters within clusters of general transcription factors. The work defines physical parameters and mechanisms of long-range gene activation.

    Why it matters: Directly visualizes how distal enhancers contact promoters and trigger transcriptional bursting.

  3. biorxiv.org53

    FLASH X-rays preserve neutrophil chromatin to boost antitumor immunity

    FLASH X-rays at 8 Gy, unlike an equal conventional dose-rate dose, triggered a robust abscopal antitumor effect with anti-PD-1 in a bilateral subcutaneous tumor model in mice. The ultrashort dose delivery conserved neutrophil chromatin compaction, inhibiting neutrophil extracellular trap formation and reversing NET-mediated CD8+ T-cell exclusion, while conventional or split-dose FLASH caused chromatin hyper-relaxation and NETosis. Radiation-induced chromatin relaxation in neutrophils emerges as a determinant of radioimmunotherapy outcome.

Oct 13Tue
  1. biorxiv.org44

    Radiotherapy Reshapes the 3D Genome in Medulloblastoma Cells

    A single 2 Gy dose reorganized the 3D genome and rewired transcription and protein expression in ONS-76 medulloblastoma cells, shifting chromatin towards active A compartments, forming new TAD boundaries, and transiently strengthening existing ones while global genome organisation stayed stable. Integrated RNA-seq, proteomics, and Micro-C pointed to LAMB3 and AKR1B10 as candidate mediators of radioresponse that stayed elevated after fractionated irradiation. This is the first genome-wide picture of radiation-induced chromatin reorganisation in a medulloblastoma model.

    Why it matters: It gives the first genome-wide map of how clinically relevant radiation remodels 3D chromatin in medulloblastoma cells.

Oct 12Mon
  1. nature.com66

    Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival

    Single-micronucleus sequencing and live-cell imaging of cancer cells, together with analyses of neuroblastoma biopsies, show that extrachromosomal DNA (ecDNA) residing in micronuclei constrains tumor cell fitness. In patients with neuroblastoma, micronuclear ecDNA was associated with favorable survival. The work identifies micronuclear localization of ecDNA as a feature linked to reduced tumor fitness rather than unchecked growth.

    Why it matters: Links ecDNA compartmentalization in micronuclei to tumor fitness and patient survival in neuroblastoma.

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.org68

    Disrupted chromatin architecture blocks B lymphopoiesis in Down syndrome

    Three-dimensional genome architecture organizes human fetal haematopoiesis and explains the B-lineage defect in Down syndrome. Using ChromE-seq, a new single-cell assay jointly profiling chromatin conformation and transcription, the authors built a multimodal atlas of ~400,000 haematopoietic cells from disomic and trisomy 21 fetal liver. Trisomy 21 disproportionately disrupted B-lineage architecture, weakened an EBF1-centred regulatory circuit, and deleting a T21-sensitive EBF1 loop anchor reproduced the CLP-to-B-progenitor bottleneck seen in T21.

    Why it matters: Links 3D chromatin architecture to lineage priming and identifies an EBF1 circuit behind the trisomy 21 B-cell defect.

Oct 10Sat
  1. biorxiv.org60

    A mitotic restriction point for extrachromosomal DNA hubs in cancer cells

    Mitosis is the critical window in which extrachromosomal DNA (ecDNA) hubs are organised and inherited across cell generations. An optical screen identified the mitotic-entry regulator WEE1 as a key regulator of hub integrity and oncogene expression, with CDK1- and CDK2-regulated programmes cooperating to carry unresolved damage into mitosis and reorganise ecDNA tethered to mitotic chromosomes. Live-cell imaging shows hub architecture is remodelled during mitosis and maintained through interphase, a coupling conserved across cancer types and ecDNA-associated oncogenes, defining a mitotic restriction point and a potential therapeutic window for ecDNA-driven cancers.

  2. biorxiv.org62

    Systematic mapping of enhancers, silencers, and topological elements with prime editing deletion screens

    Swap-seq, a method combining pooled twin prime editing with flow-sorting, deletes hundreds of endogenous regulatory sequences and measures their quantitative effects on nearby gene expression. Applied to PPIF regulation in THP-1 monocytes, it quantifies distal and intronic enhancers, characterizes CTCF insulators, and uncovers a silencer that represses neighboring enhancers through HDAC-mediated mechanisms, with hundreds of genomic elements sharing its signatures. The resulting data show sequence-to-function models capture local element activity but fail to link elements to distal target genes.

    Why it matters: It delivers a generalizable deletion-screening tool and a benchmark showing sequence-to-function models miss distal gene targeting.

  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. biorxiv.org48

    Centromeric islands constrain CENP-A domain size and position

    Deleting the ~50-kb retroelement-rich island Giglio from Drosophila centromere 3 leaves centromere identity and overall CENP-A levels intact at the native locus, showing the island is dispensable for identity. The deletion instead increases variability in CENP-A chromatin organization, yielding heterogeneous domain sizes and preferential redistribution of CENP-A into the adjacent dodeca satellite. Centromeric islands thus constrain the size and position of the CENP-A domain rather than specifying centromere identity.

  2. biorxiv.org58

    High-throughput identification of chromatin-opening transcription factors

    Pooled CRISPR activation of endogenous transcription factors in mouse embryonic stem cells reveals which TFs can open chromatin when newly expressed. After screening guides targeting 240 developmental TFs, the authors profiled gene expression and chromatin accessibility in ~140,000 single cells for 60 TFs. Some, like Cdx2 and Sox10, open distal sites on their own, while others require co-TFs through preexisting heterogeneity or hierarchical activation, such as Sox7 inducing Gata6.

  3. Mol Cell65

    Mechanistic insights into chromatin modulation by the "orphan" remodeler ATRX.

    A cryo-EM structure of human ATRX bound to the nucleosome shows how the remodeler embraces and unwraps ~18 base pairs of nucleosomal DNA near the entry/exit sites in the presence of ADP·BeF3. A phenylalanine-bearing pin-like structure on a poking helix deforms the DNA minor groove between SHL6 and SHL7, while a disordered insertion contacts the histone surface and a positively charged loop bridges cross-gyre DNA. Both the pin-like structure and the histone-contacting region proved essential for protecting cells from G-quadruplex DNA-induced stress.

  4. biorxiv.org53

    MYC drives endothelial transformation and dedifferentiation in angiosarcoma

    Endothelial-specific MYC overexpression alone was sufficient to drive angiosarcoma in mice, with the resulting pulmonary tumors showing impaired endothelial differentiation. MYC inactivation in dedifferentiated allografts induced growth arrest and restored endothelial gene expression, showing the plasticity is reversible. MYC-amplified human angiosarcomas were enriched for MYC target and cell-cycle programs and depleted of endothelial lineage signatures, matching the murine findings.

  5. 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.

  6. 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.

  7. nature.com52

    Calorie restriction reduces somatic mutation burden in mice

    Calorie restriction reduced genome-wide somatic mutation burden in mice, cutting substitution and insertion/deletion counts most strongly in intergenic, transcriptionally inactive regions and inaccessible chromatin. Duplex sequencing of liver, kidney, hepatocytes and cerebellar neurons from 19-month-old male mice under 30% calorie restriction showed that two feeding regimens with different lifespan effects reduced mutations equally, indicating mutation burden is not rate-limiting for lifespan.

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.

Oct 7Wed
  1. nature.com53

    Genome accessibility reveals disease risk that gene expression misses

    Most disease-associated genetic variants act not on genes directly but on genome accessibility that changes gene expression. Simultaneous analysis of gene expression and accessibility in 10 million immune cells from 1,108 people now links disease-associated changes in accessibility to gene expression. The work gives a route to detecting disease risk that expression data alone misses.

  2. 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.

  3. Nature82

    tRNA dosage regulates lineage dependency and resistance in prostate cancer.

    tRNA1Arg(UCU) regulates lineage transitions and therapy resistance in prostate cancer. It reprograms lineage dependence and can be tuned to restore sensitivity to androgen receptor-targeting therapies, operating through a translational program centred on SWI/SNF chromatin remodellers, with TARDBP and ZSCAN29 binding its genomic locus. In patients, tRNA1Arg(UCU) is downregulated in neuroendocrine prostate cancer, and its loss is associated with accelerated metastasis and poor survival.

    Why it matters: Links a specific tRNA to lineage plasticity and a route to restoring androgen receptor therapy sensitivity.

Oct 6Tue
  1. biorxiv.org47

    The mammalian genome is punctuated by regularly spaced nucleosome islands

    A deep-learning model trained on genome-wide nucleosome maps from mouse embryonic stem cells predicts nucleosome occupancy from primary DNA sequence alone and separates shared biological signal from assay-specific noise. In silico mutagenesis pinpointed positioning regions built from short 5-to-20-base-pair motifs in dense regulatory windows, with CCCTC-binding factor motifs in SINEs, zinc-finger-bound motifs in LINEs, and microsatellite repeats acting as potent organizers of nucleosome phasing. This extends sequence-encoded nucleosome architecture, known in yeast, to mammalian genomes.

Oct 5Mon
  1. 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
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. Nature72

    Human genetics implicates a BACH2-NRF2 axis in fetal haemoglobin activation.

    A multi-ancestry genome-wide association study of fetal haemoglobin (HbF) levels in 28,279 individuals identified 91 conditionally independent associations across 12 genomic regions. The high-HbF-linked variant rs1010474-C reduces BACH2 expression, and perturbing or inhibiting BACH2 raises HbF: BACH2 restrains γ-globin activation, while its loss enhances NRF2 occupancy at the γ-globin genes, independently of BCL11A. Editing the overlapping BACH2 and NRF2 promoter motifs can selectively activate or repress γ-globin, pointing to a new targetable axis for HbF induction.

    Why it matters: Identifies BACH2-NRF2 as a BCL11A-independent, genetically supported mechanism for activating fetal haemoglobin.

  4. 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.

  5. 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.

  6. 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.com64

    Transcription pause and elongation regulators mediate somatic hypermutation

    Somatic hypermutation depends on recruitment of activation-induced deaminase to chromatin and on a stalled polymerase II substrate; the molecular factors and mechanisms mediating both have now been identified. The work names the transcription pause and elongation regulators involved, filling a mechanistic gap in how mutation targets are generated during antibody diversification.

    Why it matters: Identifies the transcription regulators that create the substrate for activation-induced deaminase in somatic hypermutation.

  3. nature.com63

    Human genetics implicates a BACH2–NRF2 axis in fetal haemoglobin activation

    A multi-ancestry GWAS of fetal haemoglobin (HbF) levels in 28,279 individuals across European, African and Asian cohorts identified 91 conditionally independent signals at 12 loci, including BACH2 as a new regulator. BACH2 restrains NRF2-mediated transcriptional activation of the γ-globin genes HBG1 and HBG2, defining a BACH2–NRF2 axis in HbF regulation. The finding adds a genetically nominated activator pathway to the known repressors and suggests therapeutic targets for sickle cell disease and β-thalassaemia.

    Why it matters: It nominates a new genetically validated activator, BACH2, of fetal haemoglobin, opening therapeutic avenues for haemoglobin disorders.

  4. 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.org60

    Gene flux shapes diversity and evolution of the ancient 17q21.31 inversion polymorphism

    The common 979-kb 17q21.31 inversion in humans, long treated as a recombination-suppressing block, in fact permits ongoing gene flux between H1 and H2 haplotypes. Single-cell sperm sequencing showed near-complete suppression of single crossovers, but two-switch events of 17-150 kb occurred throughout the inversion at rates above genome-wide estimates, and 99 H1-H2 recombinant haplotypes were found in All of Us genomes. Recombinant haplotypes showed H2 additively increases female crossover rates across chromosomes, an effect not explained by KANSL1 duplications, and gene flux dates to roughly 100-500 thousand years ago.

Sep 28Mon
  1. biorxiv.org67

    Disruption of the ARID1A-containing SWI/SNF complex reprograms tumor-associated macrophages and enhances immunotherapy response

    Disrupting the SWI/SNF chromatin remodeling complex in tumor-associated macrophages reprograms them and improves checkpoint blockade immunotherapy. Pharmacologic inhibition of SWI/SNF ATPase activity slowed tumor growth, and deleting the SWI/SNF subunit Arid1a in myeloid cells was sufficient to suppress tumor progression and enhance checkpoint blockade response. The reprogramming involved reduced enhancer accessibility at poor-prognosis genes such as Spp1, increased accessibility at interferon-stimulated gene promoters, elevated CD86, and required CD86 costimulation and CD8+ T cells.

    Why it matters: It identifies a druggable epigenetic target in macrophages that improves checkpoint blockade response.

  2. biorxiv.org54

    Structural variation in repeat elements is widespread in normal human tissues and in tumorigenesis

    Mosaic structural variants occur in all individuals and germ layers, with long- and short-read WGS of 47 normal tissues (168 samples) showing a median 285.2 kb affected per genome. Most variants were repeat-mediated and 8.3% overlapped functional elements, enriched relative to germline variants. Repeat alterations measured from short reads across 15 cancer types matched normal mosaic variation in scale and enabled tumor tracking in cell-free DNA.

    Why it matters: Quantifies repeat-driven mosaic structural variation in normal tissues and shows repeat changes in cell-free DNA can monitor tumors.

  3. biorxiv.org62

    Structural polymorphism and population-variable coding capacity of HERV-K(HML-2) in human pangenomes

    Haplotype-resolved long-read assemblies from 292 donors reveal extensive structural polymorphism in HERV-K(HML-2) proviruses: tandem arrays at 13 loci with up to six copies each, a previously undescribed full-length provirus at 8q11.23, and intact open reading frames in many individuals where reference genomes carry disruptive mutations. Short-read genotyping left 32.5% of donor-variant pairs unresolved at sites tied to viral reading frames. HML-2 expression studies should account for the coding alleles each individual carries.

    Why it matters: Reference-based short-read methods miss HML-2 structural and coding variation that affects interpretation of HERV expression in disease.

  4. biorxiv.org61

    A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity

    Suppressive neutrophils (PMN-MDSCs) depend on mSWI/SNF chromatin remodeling to maintain their identity, and two orally bioavailable mSWI/SNF ATPase antagonists, a degrader and a catalytic inhibitor, produced immune-dependent tumor control in syngeneic models, including tumors resistant to PD-1 blockade. Treatment depleted intratumoral PMN-MDSCs, restored functional CD8+ T cells, enhanced checkpoint therapy without overt toxicity, and blocked PMN-MDSC expansion in mouse and human cells. Mechanistically, antagonism collapsed chromatin accessibility and PU.1/C/EBPβ occupancy at regulatory elements sustaining PMN-MDSC identity.

    Why it matters: It identifies a druggable chromatin dependency of PMN-MDSCs and shows it can restore antitumor immunity and checkpoint response.

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