Biology subjects

Dahl, A.

Publications and source records attributed to Dahl, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Understanding genetic and environmental complexity in phenotypic resemblance across relatedness in population-scale data

A fundamental feature of a trait's variation in a population is how its phenotypic similarity scales with genetic relatedness. Under a strictly additive model of genetic architecture, phenotypic similarity increases linearly with genetic relatedness, with a slope equal to the heritability; this underpins approaches to heritability estimation from sibling IBD regression to Haseman--Elston regression and GREML. Empirically, however, the relationship is not linear for many traits (Kemper et al., 2021). Biobank-scale measurements make fine-grain observations of the phenotypic covariance versus genetic relatedness relationship increasingly feasible, motivating new theory to understand these new empirical observations. Here we evaluate how three processes might introduce non-linearities to the relationship: imperfect tagging of causal variants, assortative mating, and multi-generational shared environments. Through theoretical modeling and simulation, we find each process acts within pedigree classes differently, introducing non-linearities through impacts on the local slope and intercept of phenotypic covariance on genetic relatedness: imperfect tagging lowers the slope among distant relatives, shared environments elevates the intercepts for closer relatives, and assortative mating changes both the slope and intercept. Within these models, we explore a variety of scenarios, finding cases where the local slope of covariance on relatedness values among unrelated pairs versus among siblings can reach nearly three times the raw heritability, and building insight to where heritability estimates are likely to be biased. We then examine these patterns across a range of traits in the UK Biobank, with a supplementary analysis in All of Us. The shape of the relationship varies widely across traits, with profiles exhibiting features found under each of the theoretical mechanisms we explored. Overall, we conclude disentangling these multiple overlaid processes will be necessary to fully understand how phenotypic similarity increases with genetic relatedness in large cohorts.

genetics↗

bioRxiv2026

Locus-specific gene-context interactions improve polygenic prediction

Polygenic scores (PGS) are a primary output of large-scale genetic studies and are being deployed in clinical and non-clinical settings. However, current PGS assume simple additive models that ignore context-specific genetic effects, which likely reduce their accuracy and robustness. To address this, we developed PGSC, a PGS framework to incorporate locus-specific gene-context interaction effects (GxC). Simulations show PGSC is robust under the additive model and outperforms PGS in realistic settings. Using sex, age, and statin treatment status as contexts in UK Biobank, we find that PGSC outperforms PGS on average across 48 traits, with substantial improvement in some cases, such as GxSex for testosterone, GxAge for bilirubin, and GxStatins for LDL cholesterol. PGSC consistently outperforms a simple genome-wide GxC model, ampPGS, which only outperforms PGS when a context uniformly amplifies all genome-wide additive effects. Critically, PGSC improvements replicate across ancestries in the UK Biobank and in an external cohort, the Mount Sinai Million Health Discovery Program. Finally, we test robustness to log-scale phenotypes and find that ampPGS gains vanish, while the locus-specific GxC components in PGSC persist. Overall, PGSC is a simple, robust framework that demonstrates GxC effects can improve out-of-sample PGS prediction and is a step toward precision treatment.

genetics↗

bioRxiv2026

Nup153 regulates neuronal responsiveness through HDAC1-mediated epigenetic modulation

Neural activity-dependent gene regulation is central to the development of neural networks and neuronal plasticity. Induction of activity-dependent gene programs is equally important as repression of these programs, and both need to be balanced carefully. However, little is known about how repressive mechanisms modulate neuronal responsiveness across the genome before stimulation. Here, we identify nucleoporin-dependent regulation of neuronal responsiveness, in which Nup153 represses neuronal genes including activity-regulated genes (ARGs), in the basal state. By characterizing the genome-wide landscape of chromatin accessibility, histone modifications and Nup153 chromatin binding, we show that Nup153 bidirectionally regulates chromatin states through both basal activity-dependent and -independent mechanisms and influences associated genes. Mechanistically, Nup153 associates with HDAC1 to modulate histone acetylation and chromatin accessibility at target regulatory regions. Our data suggests Nup153 organizes chromatin states that regulate neuronal gene programs involved in maintaining neuronal responsiveness. TeaserNup153 primes neuronal responsiveness through multi-layered epigenetic regulation.

neuroscience↗

bioRxiv2026

MetaHarmonizer: robust biomedical metadata harmonization and a contamination control for inflated LLM performance on public benchmarks

Public biomedical repositories hold substantial reuse potential, but inconsistent metadata routinely blocks integration across studies. Recent LLM-based harmonization approaches address scale but suffer from non-determinism, hallucinated ontology terms, and, in their highest-accuracy configurations, dependence on proprietary APIs or labeled fine-tuning data. A more fundamental concern is that LLM accuracies on widely-used public benchmarks may substantially inflate transferable capability: under a contamination-controlled evaluation protocol we developed, the apparent LLM-only advantage on the GDC schema-mapping benchmark is inverted and three out of five LLMs recovers 80-100% of GDC identifiers from zero-schema context, suggesting direct memorization. Building on this insight, we present MetaHarmonizer, an automated metadata harmonization system designed to be robust by construction: SchemaMapper aligns attribute names across schemas, and OntologyMapper standardizes values to controlled vocabularies. Both modules implement a multi-stage cascade that escalates to more resource-intensive methods only when earlier stages fall short, with all candidates grounded in pre-defined controlled vocabularies to preclude hallucinated outputs and LLMs used only as bounded preprocessing components rather than inference-time dependencies. On the GDC schema-matching benchmark, SchemaMapper with the deployment-optimized LLM-generated alias dictionary achieved 71.6% Top-1 accuracy and the higher Recall@GT than Magneto bipartite variants, recovering significantly more ground-truth mappings; with the best performing alias dictionary, it reached the highest Top-1/Top-5/Recall@GT, and also matched the best Magneto reranker (fine-tuned LLM-reranker) on MRR; and it also outperforms LLM-only performance under contamination-controlled conditions. On four EFO benchmarks, OntologyMapper achieved 77.9-95.5% Top-1 accuracy, outperforming text2term by up to 16.4 pp and direct LLM inference (against the smaller corpus) by 19.2 pp because memorization is not a viable shortcut for this task. Across both modules, calibrated confidence scores separate correct from incorrect predictions (AUC 0.73-0.94), enabling principled human-in-the-loop triage. Inference is fully local, deterministic, and computationally efficient - seconds on schema mapping and under a minute for ontology mapping of up to [~]7,000 terms against the pre-indexed 33,230-term corpus. Released as a Python package with a domain-agnostic architecture, MetaHarmonizer provides a scalable foundation for improving the FAIRness of biomedical data and enabling cross-study integration, alongside an evaluation methodology applicable to any LLM-augmented bioinformatics benchmark built on public benchmarks.

bioinformatics↗

bioRxiv2026

Optimizing phenotype scale improves genetic analyses in large-scale biobanks

Large-scale biobanks have enabled increasingly complicated genetic analyses across thousands of phenotypes. However, studies rarely consider the appropriate phenotype measurement scale, a problem that can drastically affect inferences on genetic architecture. Here, we introduce SIQReg, a practical solution to this classical problem, which learns a data-driven phenotype scale by minimizing heterogeneity across phenotype quantiles. Applied to complex traits in UK Biobank, SIQReg rejects the default scale for 24/25 traits. Generally, SIQReg scales lie between default and logarithmic, indicating that default-scale traits are neither purely additive nor purely multiplicative. We show that SIQReg improves both non-additive and additive genetic analyses. SIQReg eliminates most non-additive genetic signals (such as 97% of vQTL and 76% of quantile-dependent TWAS genes), indicating they may be statistical artifacts, while preserving biologically plausible non-additive signals. Simultaneously, SIQReg improves power to detect additive signals, increasing GWAS loci, TWAS genes, and PGS prediction accuracy by 11%, 13%, and 10%, respectively, and identifies 50% more high-risk individuals. These gains replicate across ancestry groups. Our results establish SIQReg as a principled approach to phenotype scale transformation that improves genetic analyses of complex traits.

genetics↗

bioRxiv2026

Mesenchymal stroma cell-derived stem cell factor mediates cross-species compatibility of the hematopoietic stem cell niche.

The regulation of human hematopoietic stem cell (HSC) function within its native bone marrow microenvironment remains poorly understood due to the limitations of existing humanized models. Here, we present a non-conditioned human HSC xenotransplantation platform that serves as a physiologically relevant in vivo surrogate to study these complex cellular interactions. Using this system, we uncover a dynamic, cross-species communication between human HSCs and the murine niche, revealing a profound cellular and molecular plasticity of the bone marrow microenvironment in response to humanization. Upon engraftment, platelet-derived growth factor receptor alpha positive (Pdgfra+) mesenchymal stromal cells (MSCs) undergo significant numerical expansion and a major transcriptional shift, transitioning from a mixed adipo- and osteo-primed state toward a leptin receptor positive (Lepr+) predominantly adipo-primed, hematopoiesis-supporting signature. Functional validation demonstrates that this niche plasticity is a critical determinant of stem cell engraftment: the targeted depletion of Lepr+ MSCs or the genetic deletion of stem cell factor results in the rapid mobilization and lack of engraftment of human HSCs, respectively. Our findings establish niche plasticity as a primary regulator of human HSC function and demonstrate the utility of this cross-species platform as a modular genetic toolbox for precise in vivo engineering of the bone marrow microenvironment. Ultimately, this adaptable system provides a powerful framework for elucidating human stem cell biology and advancing bone marrow transplantation therapies.

cell biology↗

bioRxiv2026

Latent neural network representations of the brain reflect broad-scale adolescent phenotypic variation

The adolescent brain is attuned to social and environmental exploration, allowing behavioral adaptation as experiences shape lasting patterns of morphological organization. Using a convolutional neural network on longitudinal structural MRI data, we assess the early part of this developmental window and derive latent brain representations reflecting patterns of structural variability linked to personal, social, and neighborhood conditions in adolescence. These representations offer a flexible framework for mapping brain-trait associations in adolescence and beyond.

neuroscience↗

bioRxiv2026

Tissue composition shapes differential skeletal integration strategies during axolotl limb regeneration

Limb regeneration requires rebuilding the missing structures and integrating them with stump tissues. Osteoclast-mediated tissue resorption is essential for skeletal integration during regeneration. However, it is unknown if skeletal tissue composition impacts its resorption and, if so, how it is regulated. Here, we show that osteoclast-mediated skeletal resorption is activated in amputations damaging the diaphysis, but not the epiphysis, of skeletal elements. We found that amputations in the calcified diaphysis trigger the sustained expression of RANKL and the chemokine Loc483, and that the latter is sufficient to induce osteoclast presence in non-resorbing amputations. Finally, our data suggests that the transcriptomic profile of the apical ectodermal cap is impacted by the tissues injured by the amputation. Overall, our work reveals that tissue composition at the amputation plane shapes adaptations of the regenerative program, which ultimately contribute to the near-seamless tissue integration of the regenerating axolotl limb regardless of the amputation position.

developmental biology↗

bioRxiv2026

Renin is critical for Renin Lineage Cell Plasticity and Migration in experimental crescentic Glomerulonephritis

Key PointsO_LIRenin deficiency in renin-lineage cells worsened crescentic injury and impaired cell migration, revealing a protective role for renin in crescentic glomerulonephritis. C_LIO_LILoss of renin shifted renin-lineage cells signaling toward interferon/STAT1-driven C_LIO_LIRenin-lineage cell ablation in crescentic glomerulonephritis induced a less inflammatory disease time-course. C_LI BackgroundThe adult juxtaglomerular renin-lineage cell (RLC) niche contributes to intraglomerular repair after injury, but their role in highly inflammatory crescentic glomerulonephritis (cGN) remains unclear. While angiotensin II-AT1R signaling promotes fibrosis and inflammation, the contribution of the RLCs, and of renin expression within RLCs, to cGN outcome has not been investigated. MethodsWe used tdTomato lineage-tracing to track RLCs in wild-type (WT) and renin-knockout (RenKO) mice following cGN induction. RLC migration and glomerular injury were quantified histologically. Single-cell RNA sequencing was performed on isolated tdTomato-positive cells at day 10 and 21 after injury to characterize transcriptional programs. Disease progression was additionally examined in mice with diphtheria toxin A-mediated (DTA) RLC ablation. ResultsRLCs were detected within injured glomeruli during cGN, with sporadic localization to crescentic lesions. Genetic renin deletion in RLCs worsened cGN outcomes, with RenKO mice developing increased albuminuria (by 306%), crescent formation (by 50%) and podocyte loss (by 15%) by day 21 compared to WT controls. Renin-deficient RLCs exhibited a reduced intraglomerular migratory response with decreased colocalization with mesangial and podocytes cell markers. Single-cell transcriptomic analysis supports an immunomodulatory reparative phenotype in WT RLCs. In contrast, RenKO RLCs displayed enrichment of interferon-stimulated genes and pathways suppressing cell migration. RLC ablation reduced macrophage infiltration, but did not alter disease progression, suggesting compensatory cellular mechanisms. ConclusionsRenin expression supports the plasticity and injury-associated responses of RLCs during cGN. Loss of renin shifts RLCs toward an interferon-driven inflammatory and antimigratory phenotype that aggravates glomerular injury, while ablation of the RLCs may be compensated without major outcome changes.

pathology↗

bioRxiv2026

Choice of phenotype scale is critical in biobank-based GxE tests

The importance of gene-environment interactions (GxE) for complex human traits is heavily debated. Recently, biobank-based GWAS have revealed many statistically significant GxE signals, though most lack clear evidence of biological significance. Here, we partly explain this discrepancy by showing that many GxE signals simplify to additive effects on a different phenotype scale, a classical concern that is currently underappreciated. Our results clearly distinguish GxSex effects on height, which vanish on the log scale, from GxSex effects on testosterone, where the log scale uncovers biologically meaningful female-specific effects. Across 32 phenotypes in UK Biobank, we find that scaling by a power transformation can explain 46% of PGSxSex interactions, and that simple log transformation can explain 23%, with similar results for other environments. We also show that phenotype scale can substantially impact GWAS discovery and the construction and evaluation of polygenic scores. Finally, we provide a set of guidelines to consider and choose phenotype scale in modern genetic studies.

genetics↗

bioRxiv2026

Chromosome axis protein SYCP2 recruits HORMAD2 to enable meiotic synapsis quality control in mice

Faithful chromosome segregation during meiosis depends on accurate recombination and synapsis of homologous chromosomes. These processes are monitored in mammals by checkpoint mechanisms involving the meiotic HORMA-domain proteins HORMAD1 and HORMAD2, which bind unsynapsed chromosome axes and promote activation of the DNA damage-response kinase ATR independently of DNA double-strand breaks (DSBs). However, no mechanism for axis recruitment of HORMAD1 or HORMAD2 had been demonstrated, nor had its role in checkpoint function been tested. We establish that a putative HORMAD-interacting region--the closure motif (CM)--within the chromosome-axis component SYCP2 is selectively required for HORMAD2, but not HORMAD1, localization. Deletion of the SYCP2 CM disrupts SYCP2-HORMAD2 complexes and prevents HORMAD2 axis binding without affecting axis assembly or recombination. Consequently, ATR accumulation and signaling on unsynapsed axes are reduced, and the prophase checkpoint malfunctions in a sexually dimorphic manner--causing aberrant elimination of synapsis-proficient spermatocytes and persistence of asynaptic oocytes. The phenotypes of SYCP2-CM-deficient and HORMAD2-null mice are indistinguishable, establishing the requirement for HORMAD2 axis recruitment in synapsis surveillance. We propose that axial recruitment generates a HORMAD2 scaffold that drives clustering-mediated ATR network activation independently of DSBs, thereby linking chromosome-axis architecture to synapsis quality control in mammalian meiosis.

cell biology↗

bioRxiv2025

EGFL7 promotes immune evasion in glioma through its interaction with integrin β2

Glioblastoma is the most aggressive form of malignant brain cancer, characterized by an immunosuppressive microenvironment and immune evasion. Despite the success of immune checkpoint inhibitors in other cancers, immunotherapies such as anti-PD1 have shown limited efficacy in glioblastoma, underscoring the need to identify tumor-intrinsic mechanisms that sustain this immunosuppressive microenvironment and to develop more effective therapeutic strategies targeting them. Previously, the secreted factor epidermal growth factor-like protein 7 (EGFL7) has been shown to promote brain tumor growth by affecting the glioblastoma microenvironment (GME). However, its impact on the immune system remained enigmatic. Here, we studied the role of EGFL7 in shaping the immune landscape in glioblastoma and identified the underlying molecular mechanisms it engages to drive glioma immune evasion. Single-cell transcriptomic profiling of immune cells derived of glioblastoma revealed that EGFL7 promotes an immunosuppressive GME, characterized by enhanced T cell exhaustion and polarization of macrophages towards a protumorigenic state. Proteomic profiling of EGFL7s interactome in glioma revealed its interaction with integrin {beta}2 (ITGB2), an immune cell surface receptor involved in cell adhesion and migration. Mechanistic studies uncovered the central role of this interaction for immune evasion, which promoted T cell exhaustion and the polarization of macrophages towards a pro-tumorigenic state. Genetic perturbation of the EGFL7-ITGB2 axis attenuated immunosuppression and prolonged the survival of glioblastoma-bearing mice. Remarkably, a combinatorial regimen of anti-EGFL7 and the checkpoint inhibitor anti-PD1 improved the efficacy of this drug, which by itself did not improve glioma patient survival so far. In conclusion, our study provides unequivocal evidence that EGFL7 mediates immune evasion in glioma and has great potential to serve as an add-on drug target to improve immunotherapies not functional in glioblastoma patients so far.

cancer biology↗

bioRxiv2025

Functional Dichotomy of Developmental Foxp3+ Treg Cell Subsets in the Visceral Adipose Tissue of Lean and Obese Mice

Chronic inflammation and loss of Foxp3+ regulatory T (Treg) cells in the visceral adipose tissue (VAT) are hallmarks of the pathogenesis of insulin resistance and obesity. This study explores the roles of VAT Treg cells from thymic (tTreg) and peripheral (pTreg) developmental origin, revealing their opposing roles in metabolic inflammation. Obesity destabilized VAT tTreg cells, causing them to clonally expand into obesogenic Foxp3-IFN-{gamma}+ T effector cells, enhancing pro-inflammatory type 1 responses. Genetic tTreg ablation prevented this shift, promoting anti-inflammatory type 2 response, reduced body weight, and improved insulin resistance. Compared to their tTreg counterpart, pTreg cells were functionally well adapted to maintain VAT homeostasis and protect against obesity. Genetic pTreg ablation promoted spontaneous obesity symptoms even with physiological calorie intake, and worsened VAT inflammation and liver steatosis on a high-calorie diet. These findings highlight tTreg instability as a pathogenic threat and pTreg cells as crucial regulators of metabolic homeostasis. HighlightsO_LIVAT Tregs of lean mice originate from both thymic and peripheral Treg development C_LIO_LIHigh-calorie diet destabilizes tTregs that clonally expand into obesogenic IFN-{gamma}+ Th1 cells C_LIO_LIGenetic tTreg deficiency improves steady-state metabolism and prevents diet-induced obesity C_LIO_LIGenetic pTreg deficiency promotes obesity in both sexes even with normal calorie intake C_LIO_LIVAT pTregs are particularly adapted to regulate VAT homeostasis, including adipogenesis C_LI In BriefObesity and type 2 diabetes are characterized by insulin resistance, regulatory T (Treg) cell loss, and chronic inflammation in visceral adipose tissue (VAT). In this context, Yilmazer et al. dissect the functional roles of tTreg and pTreg cells. They show that VAT pTreg cells are particularly adapted to exert non-redundant homeostatic functions, and that pTreg deficiency predisposes to obesity even with normal calorie intake. In contrast, VAT tTreg cells can contribute to local inflammation by dedifferentiating into Foxp3- Th1-polarized effector cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/642664v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@19c740corg.highwire.dtl.DTLVardef@86d52borg.highwire.dtl.DTLVardef@152a88org.highwire.dtl.DTLVardef@19b7b13_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Multi-omic characterization of human sural nerves acrosspolyneuropathies

Diseases of peripheral nerves termed polyneuropathies (PNPs) are common, mechanistically heterogeneous, and challenging to diagnose. Here, we integrated single nuclei transcriptomics of peripheral nerves from 33 human PNP patients and four controls (365,708 nuclei) with subcellular spatial transcriptomics. We identified novel and human-specific nerve cell type markers including unexpectedly heterogeneous perineurial fibroblasts. All PNPs shared a loss of myelinating and an increase in repair Schwann cells and endoneurial lipid-associated macrophages. Transcriptional changes affected multiple cells outside of the endoneurium across PNPs, suggesting PNPs as pan-nerve diseases. Spatially, PNPs showed a previously unknown perineurial hyperplasia and fibrotic dispersion and this was most pronounced in immune-mediated PNPs. Single cell transcriptomics supported the differential diagnosis of PNPs with potential for future unbiased diagnostic classification. One-sentence summaryThe first large-scale integrated single cell and spatial transcriptomic characterization of human peripheral nerves identifies novel cell markers and unexpected heterogeneity of perineurial cells, reveals polyneuropathies as pan-nerve diseases, and shows that single cell transcriptomics hold potential for unbiased nerve disease classification.

neuroscience↗

bioRxiv2024

AZIN2-dependent polyamine metabolism determines adipocyte progenitor fate and protects against obesity and dysmetabolism

Adipose tissue homeostasis plays a critical role in metabolic disease but the metabolic circuitry regulating adipose tissue dynamics remains unclear. In this study, polyamine metabolism emerges as an important regulator of adipose tissue pathophysiology. We identify AZIN2 (Antizyme inhibitor 2), a protein promoting polyamine synthesis and acetylation, as a major regulator of total acetyl-CoA in adipocyte progenitors (APs). AZIN2 deficient APs demonstrate increased H3K27 acetylation marks in genes related to lipid metabolism, cell cycle arrest and cellular senescence, and enhanced adipogenesis compared to wild-type counterparts. Upon high-fat diet (HFD)-induced obesity, global AZIN2 deficiency in mice provokes adipose tissue hypertrophy, AP senescence, lipid storage perturbations, inflammation and insulin resistance. IL4 promotes Azin2 expression in APs but not mature adipocytes due to diminished IL4 receptor expression in the latter. In human visceral and subcutaneous adipose tissue, AZIN2 expression positively correlates with expression of early progenitor markers and genes associated with protection against insulin resistance, while it negatively correlates with markers of lipogenesis. In sum, AZIN2-driven polyamine metabolism preserves adipose tissue health, a finding that could be therapeutically harnessed for the management of obesity-associated metabolic disease.

cell biology↗

bioRxiv2024

Extensive monolayer formation depends on a subpopulation of transplanted human iPSC-derived RPE cells

Loss of the retinal pigment epithelium (RPE) in the eye leads to photoreceptor dysfunction and death causing eventually vision loss. Cell replacement strategies using RPE cells derived in vitro from pluripotent stem cells (PSCs) are currently evaluated as a potential therapeutic strategy. Generation of polarized monolayers represents an essential prerequisite for proper RPE function, however, monolayer formation following transplantation of RPE cell suspensions has not been systematically assessed. Using the sodium iodate mouse model of acute RPE depletion, significant increase in monolayer formation capacity of passage (P) 1 vs. P2 human iPSC-derived RPE cells was observed three weeks after transplantation. Transplant-derived monolayers showed characteristic apicobasal polarity, RPE marker expression, phagocytosis function, and preservation of the host outer nuclear layer. The cell surface marker panel CD54+/PSA-NCAM- was identified to enrich for an RPE subpopulation with high potential for monolayer formation following transplantation. Results underline the importance of defining and isolating competent cell subpopulations for successful RPE transplantation.

neuroscience↗

bioRxiv2024

Epigenome profiling identifies H3K27me3 regulation of extra-cellular matrix composition in human corticogenesis

Epigenetic mechanisms regulate gene expression programs during neurogenesis, but the extent of epigenetic remodelling during human cortical development remains unknown. Here, we characterize the epigenetic landscape of the human developing neocortex by leveraging Epi-CyTOF, a mass cytometry-based approach for the simultaneous single cell analysis of more than 30 epigenetic marks. We identify H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), as the modification with the strongest cell type-specific enrichment. Inhibition of PRC2 in human cortical organoids resulted in a shift of neural progenitor cell (NPC) proliferation towards differentiation. Cell type- specific profiling of H3K27me3 not only identified neuronal differentiation genes in the human neocortex, but also extra-cellular matrix (ECM) genes. PRC2 inhibition resulted in increased production of the proteoglycan Syndecan 1. Overall, this study comprehensively characterizes the epigenetic state of specific neural cell types and highlights a novel role for H3K27me3 in regulating the ECM composition in the human developing neocortex.

developmental biology↗

bioRxiv2024

Differences in chromatin accessibility between renal cortex and inner medulla correlate with spatial differences in gene expression and are modulated by NFAT5 function

A spatial gene expression pattern between the cortex (CTX) and inner medulla (IM) of the kidney has been observed, but the underlying mechanisms are unclear. Understanding these mechanisms is essential for elucidating renal function. Using the Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) we analyzed the open chromatin structures and the involvement of epigenetic mechanisms in mediating gene expression differences between the renal CTX and IM. We also examined the role of the nuclear factor of activated T cells 5 (NFAT5), a key regulator of hypertonicity. ATAC-seq analysis was performed on CTX and IM samples from both wild-type (WT) and NFAT5 knockout (KO) mice. This work demonstrates for the first time that these differences in gene expression between renal CTX and IM are associated with an epigenetic mechanism driven by chromatin accessibility, which is partially modulated by the nuclear factor of activated T-cells 5 (NFAT5) in mice. Furthermore, spatial localization and NFAT5-promoted chromatin accessibility correlate with differential gene expression and altered promoter binding motif enrichment in CTX and IM. This study provides new insights into the spatial and NFAT5-mediated regulation of chromatin accessibility and gene expression in CTX and IM. This work advances our understanding of kidney physiology by uncovering previously unknown epigenetic factors influencing gene expression and provides a new perspective on renal adaptive mechanisms. TRANSLATIONAL STATEMENTThe study reveals new insights into the spatial and epigenetic regulation of gene expression in the renal cortex (CTX) and inner medulla (IM) in the mouse kidney. We used the Assay for Transposase-Accessible Chromatin with High-Throughput Sequence Analysis (ATAC-seq) to identify a key role of NFAT5 in modulating chromatin accessibility and to uncover previously unknown epigenetic factors. This research enhances our understanding of renal physiology and has important implications for clinical care by providing insights into potential adaptive mechanisms in the kidney. These findings suggest future investigations targeting epigenetic signaling pathways for therapeutic intervention in renal diseases.

genomics↗