Biology subjects

Braun, S. M. G.

Publications and source records attributed to Braun, S. M. G..

6 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↗

bioRxiv2025

CRISPR screen identifies CNIH1 as a selective driver of GPCR export

G protein-coupled receptors (GPCRs), the largest family of transmembrane proteins, transduce extracellular stimuli into intracellular signaling cascades to orchestrate human physiology. The transport of newly synthesized receptors from the endoplasmic reticulum (ER) to the plasma membrane (PM) determines cellular responsiveness to incoming ligands, yet the molecular machinery governing GPCR export remains incompletely defined. Here, we combine a synchronized cargo-release assay with a genome-wide CRISPR/Cas9 screen to systematically map regulators of GPCR ER-to-PM transport. Focusing on the {delta}-opioid receptor (DOR), a prototypical class A GPCR, we identify CNIH1 as a dedicated export factor. In the absence of CNIH1, DOR is retained intracellularly with immature glycosylation, and drives reduced PM signaling. CNIH1 localizes to both ER exit sites and the Golgi, promoting the anterograde transport of a subset of class A GPCRs. Opioid receptors directly interact with CNIH1 and require its putative COPII-binding site for export. Distinct from other human cornichon homologs, CNIH1 defines a selective GPCR-sorting receptor that couples GPCR biosynthesis to signaling competence.

cell 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

mSWI/SNF promotes distal repression by titrating polycomb dosage

The mammalian SWI/SNF, or BAF complex, has a conserved and direct role in antagonizing polycomb-mediated repression. Yet, BAF appears to also promote repression by polycomb in stem cells and cancer. How BAF both antagonizes and promotes polycomb-mediated repression remains unknown. Here, we utilize targeted protein degradation to dissect the BAF-polycomb axis in embryonic stem cells on the timescale of hours. We report that rapid BAF depletion redistributes both PRC1 and PRC2 complexes from highly occupied domains, like Hox clusters, to weakly occupied sites that are normally opposed by BAF. Polycomb redistribution from highly repressed domains results in their decompaction, gain of active epigenomic features, and transcriptional derepression. Surprisingly, through dose-dependent degradation of PRC1 & PRC2 we identify both a conventional role for BAF in polycomb-mediated repression and a second mechanism acting by global redistribution of polycomb. These findings provide new mechanistic insight into the highly dynamic state of the Polycomb-Trithorax axis.

molecular biology↗