Jul 2026· Advancement of science· 0 citations· 59 references
Medicine
TL;DR
An NSD2‐H3K36me2‐EGFR‐EGFR‐ERK axis that drives cortical gliogenesis is defined and mechanistic insights into the potential contribution of NSD2 deficiency to neurodevelopmental abnormalities are provided.
Abstract
ABSTRACT Haploinsufficiency of the histone methyltransferase NSD2 is a major cause of Wolf‐Hirschhorn syndrome (WHS) and the related Rauch‐Steindl syndrome (RAUST), both of which exhibit microcephaly and intellectual disability. However, the precise role of NSD2 in brain development remains unclear. Here, we identify NSD2 as a pivotal epigenetic regulator orchestrating the transition from neurogenesis to gliogenesis in the developing mouse neocortex. Conditional knockout of Nsd2 severely impairs astrocyte production in late embryogenesis, while its overexpression promotes astrocytic fate. Integrated epigenomic and transcriptomic analyses reveal that NSD2 deposits the activating histone mark H3K36me2 directly at the Egfr promoter, sustaining EGFR expression and downstream ERK signaling—a pathway essential for gliogenesis. Pharmacological activation of ERK phosphorylation rescues the astrogliogenesis defects both in vitro and in vivo. Notably, Nsd2‐deficient mice exhibit significant deficits in learning and memory. Our findings define an NSD2‐H3K36me2‐EGFR‐ERK axis that drives cortical gliogenesis and provide mechanistic insights into the potential contribution of NSD2 deficiency to neurodevelopmental abnormalities.
It is shown that neurogenesis is disrupted at multiple stages of lineage progression in both rodent and human neural stem cell models of Huntington's disease, and a panel of clinically relevant epigenetic compounds hold promise for stage-spanning therapeutic strategies capable of modifying disease trajectory.
Jessica Rosati, A. Casamassa, G. Ruotolo et al.· Cell Death and Differentiati...· 0 citations
ABSTRACT Glioblastoma progression is driven by stemness acquisition and cellular plasticity, yet the temporal and spatial organization of these processes remains incompletely defined. In this study, single‐cell RNA sequencing, pseudotime reconstruction, spatial transcriptomics, and in vitro and in vivo functional assays were integrated to delineate the role of SOX9 during glioblastoma stemness acquisition. SOX9 expression peaked during the early astrocyte‐to‐malignant transition and declined after malignant states became stabilized. Along pseudotime, SOX9 was inversely associated with the upstream Hippo kinase module and showed phase‐dependent coupling with YAP/TAZ‐associated transcriptional programmes. Spatial analyses further revealed marked regional heterogeneity, with the strongest SOX9‐malignant coupling observed in the perivascular niche. Functionally, SOX9 gain and loss produced reciprocal changes in glioblastoma cell proliferation, migration, invasion, apoptosis, and xenograft growth, while pharmacological modulation of Hippo signalling partially rescued the effects induced by SOX9 loss. Consistent pathway‐level changes were also observed in YAP/TAZ expression and p‐YAP/YAP and p‐MOB1/MOB1 ratios, and xenograft histology showed SOX9‐associated morphological and CD68‐positive cell changes. These findings identify SOX9 as a temporally restricted regulator of glioblastoma stemness acquisition and support an early priming‐late decoupling model of Hippo‐YAP/TAZ rewiring, providing a rationale for stage‐specific and niche‐aware therapeutic targeting in glioblastoma.
Maimaitili Mijiti, Yandong Li, Aierpati Maimaiti et al.· Journal of Cellular and Mole...· 0 citations
Brain arteriovenous malformations (bAVMs) are high-risk vascular lesions prone to intracranial hemorrhage, with unclear upstream regulatory mechanisms. We integrated 5-methylcytosine (m⁵C) RNA methylation sequencing and transcriptomics in ruptured and unruptured bAVMs to identify differentially methylated non-coding RNAs. Functional validation was performed in human tissues, HUVECs, and zebrafish models. m⁵C profiling revealed global methylation remodeling in ruptured bAVMs, with enrichment of EndMT and Wnt/β-catenin pathways. USP2-AS1 emerged as a key lncRNA showing increased methylation and expression, predominantly in endothelial cells. In HUVECs, USP2-AS1 promoted EndMT-like changes and migration, while its knockdown had opposite effects. NSUN6 was identified as the primary methyltransferase mediating m⁵C modification of USP2-AS1. NSUN6-driven methylation enhanced endothelial plasticity in vitro and induced vascular abnormalities and hemorrhage in zebrafish. Mechanistically, USP2-AS1 activated Wnt/β-catenin signaling, which was essential for these effects and reversible by pathway inhibition. These findings identify a NSUN6-USP2-AS1-Wnt/β-catenin axis that drives endothelial dysfunction and bAVM rupture, suggesting potential therapeutic targets for vascular stabilization.
Ganglei Li, Mingjian Liu, Hongfei Zhang et al.· Journal of Cerebral Blood Fl...· 0 citations
Overexpression of CHCHD2 in METTL5-KO NPCs rescued proliferation and partially rescued oxidative metabolism in NPCs and ventricle formation in organoids, highlighting a previously uncharacterized connection between CHCHD2, oxidative metabolism, and METTL5-mediated regulation of human neurogenesis.
Elena M Turkalj, Gugene Kang, I. Liu et al.· Stem Cell Reports· 0 citations
ABSTRACT Radiation‐induced pulmonary fibrosis, a devastating thoracic radiotherapy sequela, features aberrant ECM deposition and irreversible loss of functional lung architecture. However, the exact molecular mechanisms governing AECII dysfunction and fate transition during RIPF remain poorly understood. Here, we identify a novel metabolic‐epigenetic‐epitranscriptomic cascade that orchestrates the pro‐fibrotic fate of AECIIs. We demonstrate that radiation exposure triggers a glycolytic shift in AECIIs, resulting in pathological intracellular lactate accumulation. This metabolic stress is directly coupled to chromatin remodeling via p300‐mediated H3K18la at the VIRMA promoter, driving its robust transcriptional activation. Consequently, elevated VIRMA promotes a pro‐fibrotic epitranscriptomic landscape by increasing m6A enrichment on the GATA3 mRNA. Recognition of this modification by the m6A reader YTHDF1 extends GATA3 mRNA half‐life. The ensuing GATA3 accumulation initiates EMT and exacerbates ECM deposition. Strikingly, utilizing AECII‐specific Virma conditional knockout mice, we confirmed the essential role of this axis in vivo; genetic ablation of Virma preserved alveolar integrity and conferred resistance to radiation‐induced fibrogenesis. Furthermore, pharmacological inhibition of the H3K18la writer p300 using C646 abrogated the fibrotic phenotype. Collectively, our findings elucidate how radiation‐induced metabolic reprogramming is durably inscribed into the epigenome to dictate cell fate, offering a therapeutic rationale for targeting the H3K18la/VIRMA/GATA3 axis in RIPF.
Junxuan Yi, Mingwei Wang, Duo Yu et al.· Advancement of science· 0 citations
The development of the mammalian cerebral cortex is tightly regulated by epigenetic mechanisms. However, the role of epigenetic modifications in gene regulation and their impact on neocortical function remain poorly understood. Here, we demonstrate that Menin, encoded by the multiple endocrine neoplasia type 1 (Men1) gene, is essential for neurogenesis. Deficiency in Men1 disrupts the formation of the laminated neocortex, particularly in the upper-layer neurons. In Men1-deficient late-born neurons, migration to their final positions is impaired, accompanied by defective neuronal polarization. Mechanistic studies reveal that Menin regulates global chromatin accessibility at transcriptional start sites of genes critical for neuronal development. The loss of Menin primarily reduces H3K4me3 deposition at promoter regions. Notably, complementation with EphA4 in late-born neurons mitigates polarization defects in the context of Men1 deficiency. These findings support the importance of Menin in corticogenesis, providing insight into the formation of the cerebral cortex.
Shuzhong Wang, Kai Zhuang, Liu-Rong Chen et al.· Cell Reports· 0 citations
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