Biology subjects

Grosschedl, R.

Publications and source records attributed to Grosschedl, R..

5 recordsLinked to original sources

bioRxiv2026

EBF1 regulates the blood-thymus barrier and ETP influx through Claudin-5 in thymic endothelial cells

The blood-thymus-barrier (BTB) is essential for regulating the entry of thymic-seeding progenitors into the thymus, an organ lacking self-renewing T cell progenitors. Here, we identify Early B-cell factor 1 (Ebf1), a transcription factor with established roles in hematopoiesis, as specifically expressed in thymic endothelial cells. Tie2-Cre-mediated deletion of Ebf1 results in a significant reduction of early thymic progenitors (ETPs), despite unaltered bone marrow lymphoid progenitor populations, unaltered thymic stromal subset frequencies, and intact downstream thymocyte differentiation. Transcriptome analysis of Ebf1-deficient thymic endothelial cells reveals increased expression of tight-junction-associated genes, in particular Cldn5, a key tight-junction component that restricts the BTB. Consistent with reduced BTB permeability, ETP subset analysis demonstrates a proportional reduction in the ETP1 fraction, the progenitor population that resides in closest proximity to thymic endothelial cells at the cortico-medullary junction. Together, our study implicates Ebf1 in the regulation of the BTB permeability, through modulation of tight-junction programs, thereby enabling thymus-seeding progenitor entry.

immunology↗

bioRxiv2025

Lineage-determining transcription factors constrain cohesin to drive multi-enhancer oncogene regulation

Multiple enhancers, often located across vast genomic distances, regulate key genes. However, how chromatin topology organization at individual alleles enables cell-type-restricted multi-enhancer gene regulation remains unclear. Using acute protein degradation and time-course population-average chromatin conformation capture in lymphoma, we found that the B-cell- lineage-determining transcription factor EBF1 preferentially positions multiple enhancers at loci containing sparsely distributed genes essential for B-cell identity and oncogenesis. Our time-resolved sub-diffraction optical chromatin architecture tracing of >100,000 alleles in individual lymphoma cells further revealed diverse topological conformations facilitating multi-enhancer interactions. Mechanistically, we found that positioning of enhancers at allelic topological centers is required for their interactions with target promoters, with EBF1 serving as a barrier to the loop-extruding cohesin on enhancers. These findings, which we demonstrate their generalizability to the T-cell-lineage-determining transcription factor TCF1 in T-cell leukemia, suggest that lineage-determining transcription factors radially position enhancers and promoters to enable multi-enhancer regulation of key oncogenes.

cancer biology↗

bioRxiv2023

Sema7A and Sema4D Heterodimerization is Essential for Membrane Targeting and Neocortical Wiring

Disruption of neocortical circuitry and architecture in humans causes numerous neurodevelopmental disorders. Neocortical cytoarchitecture is orchestrated by various transcription factors such as Satb2 that control target genes during strict time windows. In humans, mutations of SATB2 cause SATB2 Associated Syndrome (SAS), a multisymptomatic syndrome involving intellectual disability, speech delay, epilepsy and craniofacial defects. We show that Satb2 controls neuronal migration and axonal outgrowth by inducing the expression of the GPI-anchored protein, Sema7A. We find that heterodimerization with Sema4D increases targeting of Sema4D to the membrane and is required for Sema7A function. Finally, we report that membrane localization and pos- translational modification of the Sema7A-Sema4D complex is disrupted by a novel de novo mutation in Sema4D (Q497P) that is associated with epilepsy in humans. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/527998v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@db698org.highwire.dtl.DTLVardef@4ee980org.highwire.dtl.DTLVardef@c3d9d6org.highwire.dtl.DTLVardef@12a135_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LISema7A is a direct Satb2 target that drives neuronal migration and axon outgrowth C_LIO_LISema7A exerts its effect by heterodimerizing with Sema4D at neurites and growth cones C_LIO_LISema7A increases cell surface localization of Sema4D C_LIO_LIDe novo human Sema4D-Q497P mutation causes epilepsy, inhibits post-translational processing & surface localization C_LI eTOCSema7A is a direct target of the transcription factor Satb2. Sema7A promotes normal migration and axon outgrowth in cortical neurons by modulating reverse signaling via Sema4D. These processes are dependent on Sema7A-Sema4D heterodimerization and membrane localization; insufficient transcription of Sema7A or incomplete glycosylation of Sema4D inhibit this progression.

neuroscience↗

bioRxiv2022

A new type of transcriptional reprogramming by an IRF4 mutation in lymphoma

SUMMARY PARAGRAPHDisease-causing mutations in genes encoding transcription factors (TFs) are a recurrent finding in hematopoietic malignancies and might involve key regulators of lineage adherence and cellular differentiation1-3. Such mutations can affect TF-interactions with their cognate DNA-binding motifs4, 5. Whether and how TF-mutations impact upon the nature of binding to TF composite elements (CE) and influence their interaction with other TFs is unclear. Here, we report a new mechanism of TF alteration in human lymphomas with perturbed B cell identity. It is caused by a recurrent somatic missense mutation c.295T>C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cell-differentiation and -activation6, 7. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF composite elements (CEs). Furthermore, IRF4-C99R thoroughly modifies IRF4 function, by blocking IRF4-dependent plasma cell induction, and up-regulating disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single arginine mutation creates a complex switch of TF specificity and gene regulation. These data open the possibility of designing specific inhibitors to block the neomorphic, disease-causing DNA-binding activities of a mutant transcription factor.

cancer biology↗

bioRxiv2018

Active intermixing of indirect and direct neurons builds the striatal mosaic

The striatum controls behaviors via the activity of direct and indirect pathway projection neurons (dSPN and iSPN) that are intermingled in all compartments. While such mosaic ensures the balanced activity of the two pathways, how it emerges remains largely unknown. Here, we show that both SPN populations are specified embryonically and progressively intermix through multidirectional iSPN migration. Using conditional mutants of the dSPN-specific transcription factor Ebf1, we found that inactivating this gene impaired selective dSPN properties, including axon pathfinding, whereas molecular and functional features of iSPN were preserved. Remarkably, Ebf1 mutation disrupted iSPN/dSPN intermixing, resulting in an uneven distribution. Such architectural defect was selective of the matrix compartment, revealing that intermixing is a parallel process to compartment formation. Our study reveals that, while iSPN/dSPN specification is largely independent, their intermingling emerges from an active migration of iSPN, thereby providing a novel framework for the building of striatal architecture.

neuroscience↗