Biology subjects

Soldati, H.

Publications and source records attributed to Soldati, H..

5 recordsLinked to original sources

bioRxiv2026

Distinct epigenetic and metabolic states reflect the regional identity of adult neural stem cells and prime their fate

Neural stem/progenitor cells (NSPCs) in the adult mouse brain reside in distinct niches, including the dentate gyrus (DG) and subventricular zone (SVZ). The contribution of cell intrinsic versus extrinsic factors to distinct fates of NSPCs and their neuronal progeny remains largely unknown. We here show that DG- and SVZ-derived NSPCs retain niche-specific chromatin accessibility states that predict neuronal subtype specification. Furthermore, metabolic profiling and gene expression analyses comparing DG- and SVZ-derived NSPCs revealed differences in carnitine synthesis pathways and lipid metabolism. Supplementation with carnitine or S-adenosylmethionine (SAM) induced chromatin remodeling via histone modifications, indicating that a metabolic-epigenetic cross-talk determines regional neuronal identity. Our findings show that NSPCs are intrinsically programmed by chromatin and metabolic states, and that metabolic interventions alter epigenetic landscapes and fate potential.

cell biology↗

bioRxiv2026

A Glycosylation-Dependent Checkpoint Restrains Intestinal Intra-Epithelial Lymphocyte Activation

Intraepithelial lymphocytes (IELs) are abundant in the intestinal epithelium, where they maintain barrier integrity and provide immune defense. Because of their potent cytotoxic and effector potential, IEL activity must be tightly controlled to prevent tissue damage. However, the mechanisms that calibrate IEL responsiveness remain unclear. Here, we identify glucosaminyl (N-acetyl) transferase 2 (Gcnt2) as a key restrainer of both natural and induced gut IEL. Among T cells, Gcnt2 is uniquely enriched in the intestine and partly dependent on retinoic acid signaling. GCNT2-mediated branched glycosylation marks IELs with signatures of tissue adaptation and reduced TCR responsiveness. Genetic ablation of Gcnt2 enhanced IEL degranulation, cytokine production, and cytotoxicity upon stimulation, improving bacterial clearance and limiting infection-induced disease, while aggravating the pathological consequences of strong T cell activation. Mechanistically, GCNT2-mediated glycosylation of CD45 reduced its phosphatase activity, thereby dampening TCR signaling and effector responses. Together, these findings reveal GCNT2 as a glycosylation-dependent checkpoint that fine-tunes IEL effector functions, uncovering a novel mechanism by which the intestinal immune system balances responsiveness and tolerance. SummaryGCNT2-mediated I-branching glycosylation of CD45 restrains IEL activation.

immunology↗

bioRxiv2025

Redundancy masks functional specificity of SMARCD paralogs in neurodevelopment

The SWI/SNF complex is an essential chromatin remodeler that regulates DNA accessibility during brain development. Through combinatorial assembly of subunits encoded by paralogous genes, SWI/SNF complexes form diverse assemblies across and even within cell types. Although paralogs provide functional redundancy, their mutation in neurodevelopmental disorders suggests specialized roles. Focusing on the core SMARCD subunits, we find that loss of individual paralogs SMARCD1 or SMARCD3 has no impact on cortical development, and even deletion of both paralogs SMARCD1/3 in mice causes only minimal cortical defects, reflecting strong compensatory mechanisms. In neuronal differentiation models, depletion of any combination of paralogs increases the abundance of remaining subunits through protein stabilization rather than transcriptional upregulation. Despite this redundancy, rapid degradation experiments reveal distinct gene regulatory programs for each paralog. In neurons, SMARCD3 uniquely controls oxidative phosphorylation through regulation of metabolic gene networks. Finally, we identify chromatin regulators and transcription factors that associate with SMARCD1- or SMARCD3-containing SWI/SNF complexes, likely conferring paralog-specific targeting. Our findings uncover a dual logic of redundancy and specialization regulating SWI/SNF activity, providing a mechanistic basis for the selective vulnerability of paralog genes in neurodevelopmental disorders.

molecular biology↗

bioRxiv2024

CRISPR screen decodes SWI/SNF chromatin remodeling complex assembly

The SWI/SNF (or BAF) complex is an essential chromatin remodeler that regulates DNA accessibility at developmental genes and enhancers. SWI/SNF subunits are among the most frequently mutated genes in cancer and neurodevelopmental disorders. These mutations are often heterozygous loss-of-function alleles, indicating a dosage-sensitive role for SWI/SNF subunits in chromatin regulation. However, the molecular mechanisms that regulate SWI/SNF subunit dosage to ensure proper complex assembly remain largely unexplored. We performed a genome-wide CRISPR KO screen, using epigenome editing in mouse embryonic stem cells, and identified Mlf2 and Rbm15 as regulators of SWI/SNF complex activity. First, we show that MLF2, a poorly characterized chaperone protein, regulates a subset of SWI/SNF target genes by promoting chromatin remodeling activity. Next, we find that RBM15, part of the m6A RNA methylation writer complex, controls m6A modifications on specific SWI/SNF mRNAs to regulate protein levels of these subunits. Misregulation of m6A methylation causes overexpression of core SWI/SNF subunits leading to the assembly of incomplete complexes lacking the catalytic ATPase/ARP subunits. These data indicate that targeting modulators of SWI/SNF complex assembly may offer a potent therapeutic strategy for diseases associated with impaired chromatin remodeling.

molecular biology↗

bioRxiv2020

High throughput screening identifies SOX2 as a Super Pioneer Factor that inhibits DNA methylation maintenance at its binding sites

Access of mammalian transcription factors (TFs) to regulatory regions, an essential event for transcription regulation, is hindered by chromatin compaction involving nucleosome wrapping, repressive histone modifications and DNA methylation. Moreover, methylation of TF binding sites (TBSs) affects TF binding affinity to these sites. Remarkably, a special class of TFs called pioneer transcription factors (PFs) can access nucleosomal DNA, leading to nucleosome remodelling and chromatin opening. However, whether PFs can bind to methylated sites and induce DNA demethylation is largely unknown. Here, we set up a highly parallelized approach to investigate PF ability to bind methylated DNA and induce demethylation. Our results indicate that the interdependence between DNA methylation and TF binding is more complex than previously thought, even within a select group of TFs that have a strong pioneering activity; while most PFs do not induce changes in DNA methylation at their binding sites, we identified PFs that can protect DNA from methylation and PFs that can induce DNA demethylation at methylated binding sites. We called the latter "super pioneer transcription factors" (SPFs), as they are seemingly able to overcome several types of repressive epigenetic marks. Importantly, while most SPFs induce TET-dependent active DNA demethylation, SOX2 binding leads to passive demethylation by inhibition of the maintenance methyltransferase DNMT1 during replication. This important finding suggests a novel mechanism allowing TFs to interfere with the epigenetic memory during DNA replication.

genetics↗