Epigenomics (Germany)

Nonparenchymal central nervous system (CNS)-associated macrophages (CAMs) mediate immune responses at brain boundaries. Perivascular and leptomeningeal CAMs are collectively termed subdural CAMs (sdCAMs). Both sdCAMs and juxtaneuronal microglia are derived from embryonic yolk sac precursors, long-living and maintain their populations through self-renewal. Following depletion, microglia autonomously repopulate from single surviving cells. In contrast, the course of sdCAM repopulation remains poorly understood. Here, by combining multilineage fate mapping, multiomic profiling and high-resolution imaging, we demonstrate divergent repopulation dynamics between sdCAMs and microglia. Unlike microglia, sdCAMs do not renew cell-autonomously, but become transiently accessible to CCR2+Ly6C+ monocyte engraftment after niche induction in an integrin-dependent manner. Moreover, replenished monocyte-derived sdCAMs remain transcriptomically, epigenetically and functionally distinct from their embryo-derived counterparts. Finally, we present a protocol enabling selective exchange of sdCAMs, modulating disease response without functionally affecting microglia. These new insights into CNS immune biology suggest new therapeutic avenues for neuroinflammatory and neurodegenerative diseases.

The round sardinella (Sardinella aurita Valenciennes, 1847) is a widely distributed migratory pelagic fish inhabiting the Mediterranean Sea and the eastern Atlantic coasts. The species is heavily exploited and represents a valuable resource for global fisheries. In the Mediterranean area, uptakes of round sardinella are particularly high in the Ionian and Levant regions, where landings have shown fluctuating yet significant peaks in recent decades. Given its migratory nature, understanding the connectivity among populations is crucial for delineating appropriate fishery management units. Previous studies employing morphometric, meristic, and molecular analyses have yielded mixed results regarding population structuring. Here, the genetic differentiation among Eastern Mediterranean S. aurita populations was investigated using a multi-marker approach: the mitochondrial cytochrome c oxidase subunit I (COI), cytochrome b (CytB), control region (CR), and 16S ribosomal RNA (16S rRNA), and seven species-specific nuclear simple sequence repeats (SSRs). Overall, the results indicate high genetic diversity coupled with weak population structuring across the Eastern Mediterranean. These analyses aim at clarifying stock boundaries towards supporting sustainable management strategies at a regional scale for this ecologically and economically important species.

Summary The role of the peripheral immune system in Alzheimer’s Disease (AD) remains insufficiently resolved, limiting the understanding of systemic disease effects and mechanisms. Here, we employed three high-resolution single-cell techniques, including flow cytometry, single-cell RNA- and ATAC-sequencing, to investigate peripheral immunity in AD dementia and earlier stages of the AD trajectory in over 100 patients. We identified reduced humoral immune responses in AD, characterized by a diminished B cell compartment displaying an impaired activation phenotype. Classical monocytes expanded in mild cognitive impairment and early AD dementia, acquiring a NF- k B/AP-1-mediated low-grade inflammation phenotype. Our findings link peripheral dysregulation in innate and adaptive immunity at cell frequency, transcriptional and epigenetic levels to the AD trajectory and provide insights into distinct phenotypes that define AD progression in contrast to healthy aging across cohorts.

Plants in natural ecosystems are simultaneously exposed to multiple, interacting climate drivers, including rising temperature, vapor pressure deficit, atmospheric CO₂ and tropospheric ozone. However, most experimental studies rely on the static manipulation of a limited set of climate drivers (typically one or two), which restricts our ability to detect emergent or non-linear responses under future conditions.Here, we synthesize results from an ecotron study conducted at the Model EcoSystem Analyser (TUMmesa). Young Fagus sylvatica trees were exposed for three growing seasons to three dynamically simulated, regionalized climate scenarios, including a control scenario (representing an average 1987-2016 climate), a mitigation scenario (RCP2.6), and a worst-case scenario (RCP8.5). The scenarios comprised realistic seasonal and diurnal co-variation of temperature, radiation, humidity, CO₂ and O₃ at hourly resolution.Across physiological, carbon-dynamic and transcriptomic datasets, we consistently observed strong non-linear responses to increasing climate severity. While moderate future conditions (RCP2.6) induced measurable acclimation responses, plants exhibited qualitatively different responses in RCP8.5, suggesting a shift in regulatory strategies under more extreme future climates. These included threshold-like shifts in gene expression, enhanced assimilation with accelerated carbon turnover, increased belowground allocation, and altered stomatal regulation affecting transpiration and ozone uptake.Our results demonstrate that experiments manipulating only a limited set of climate drivers, or relying on extrapolation from moderate scenarios, are insufficient to predict plant responses to future climates. Instead, realistic multivariate climate simulations in ecotrons are indispensable for capturing emergent stress responses, advancing eco-physiological understanding, and improving the reliability of process-based vegetation models under future climate change.

Resolving the mRNA Encapsulation-Release Trade-off Overcoming the inherent trade-off between mRNA encapsulation and intracellular release remains a central challenge for lipid nanoparticles. Yufei Xia, Ying Ren, and co-workers rationally engineer compensatory forces in LNP (DOI: 10.1002/adma.202512235). By leveraging short-range intermolecular interactions to dynamically balance long-range Coulombic binding, reduces empty particles and ionizable lipid content, enabling efficient mRNA encapsulation and enhanced delivery for vaccination and gene-editing applications.

Altered respiratory barrier integrity and impaired lung regeneration are hallmarks of chronic obstructive pulmonary disease (COPD). To investigate the molecular mechanisms driving the impaired regeneration of alveolar epithelial progenitors in COPD, we generated whole-genome DNA methylation and transcriptome maps of sorted human primary alveolar type 2 cells (AT2) at different disease stages. Our analysis revealed aberrant DNA methylation at specific gene promoters in AT2 during COPD, which was anticorrelated with gene expression changes. Interferon signaling was the top-upregulated pathway in COPD, associated with a concomitant loss of promoter-proximal DNA methylation. Integrated pathway analysis revealed transcription factor IRF9 as the master regulator of interferon signaling in COPD. Epigenetic regulation of the interferon pathway was validated by targeted DNA demethylation of the IRF9 gene, mimicking the effects observed in COPD-derived AT2. Our findings suggest that COPD-associated DNA methylation alterations in AT2 cells may impair internal regeneration programs in lung parenchyma.

SummaryThe human basal ganglia (BG), subcortical nuclei fundamental to motor regulation and cognitive modulation, is constructed from neurons produced during gestation in the adjacent ganglionic eminences (GEs). GEs are transient structures in the ventral prenatal brain that also generate GABAergic inhibitory neurons which migrate to destinations in the BG, cortex and other destinations. This study aims to elucidate the epigenomic and 3D-genomic dynamics involved in the specification and maturation of GEs and GE-derived neurons, using single-nucleus methyl-3C sequencing (snm3C-seq), highly-multiplexed spatial transcriptomics, and chromatin+RNA single-molecule imaging. Our multi-modal data support a heterogeneous temporal progression across GE subregions, with the lateral GE (LGE) showing declining neurogenic activity in mid-gestation and caudal GE (CGE) exhibiting ongoing developmental progression through infancy. We identified regulatory programs that specify subtypes of BG principal cells, medium spiny neurons (MSN), via synchronized maturation of the 3D-epigenome. In infant brains, we found a transient short-range enriched (SE) chromatin conformation during the transition between oligodendrocyte progenitors (OPCs) and oligodendrocytes (ODCs), and a temporary shift toward Long-range Enriched (LE) chromatin conformation in projection neurons, extending previous works showing the differentiation of neurons and glial cells is associated with permanent SE and LE conformation, respectively. Lastly, we found that gene regulatory regions active in MSNs were enriched in loci associated with genetic risk for neuropsychiatric disease. Our study delineates the highly complex, lineage-specific 3D genomic dynamics in ventral progenitors and basal ganglia populations of the perinatal human brain.

Spatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naive mouse pluripotent stem cells leads to upregulation of the cysteine-generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naive to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature ageing, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Notably, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases.