FOXN1 forms higher-order nuclear condensates displaced by mutations causing immunodeficiency

Rota, Ioanna A.; Handel, Adam E.; Maio, Stefano; Klein, Fabian; Dhalla, Fatima; Deadman, Mary E.; Cheuk, Stanley; Newman, Joseph A.; Michaels, Yale S.; Žuklys, Saulius; Prevot, Nicolas; Hublitz, Philip; Charles, P. David; Gkazi, Athina Soragia; Adamopoulou, Eleni; Quasim, W; Davies, E. Graham; Hanson, Charlotte; Pagnamenta, Alistair T.; Camps, Carme; Dreau, Hélène; White, Andrea J.; James, Kieran D.; Fischer, Román; Gileadi, O.; Taylor, J.G.; Fulga, Tudor A.; Lagerholm, B. Christoffer; Anderson, Graham; Sezgin, Erdinç; Holländer, Georg A.

doi:10.1126/sciadv.abj9247

Cited by 15 publications

(12 citation statements)

References 78 publications

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“…STMN2 encodes a microtubule stability regulator, which can regulate the assembly and decomposition of tubulin, stabilize microtubules, and thus control the lengths of the neurites in cortical neurons [ 41 ]. FOXN1 is a transcription regulator that regulates the development differentiation and function of thymic epithelial cells in the thymus [ 42 ]. FOXN1 mutation-mediated immune deficiency is typically associated with severe combined immunodeficiency [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

An Analysis of the Gene Expression Associated with Lymph Node Metastasis in Colorectal Cancer

Yang,

Liu,

Jiang

et al. 2023

International Journal of Genomics

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Objective. This study aimed to explore the genes regulating lymph node metastasis in colorectal cancer (CRC) and to clarify their relationship with tumor immune cell infiltration and patient prognoses. Methods. The data sets of CRC patients were collected through the Cancer Gene Atlas database; the differentially expressed genes (DEGs) associated with CRC lymph node metastasis were screened; a protein–protein interaction (PPI) network was constructed; the top 20 hub genes were selected; the Gene Ontology functions and the Kyoto Encyclopedia of Genes and Genomes pathways were enriched and analyzed. The Least Absolute Shrinkage and Selection Operator (LASSO) regression method was employed to further screen the characteristic genes associated with CRC lymph node metastasis in 20 hub genes, exploring the correlation between the characteristic genes and immune cell infiltration, conducting a univariate COX analysis on the characteristic genes, obtaining survival-related genes, constructing a risk score formula, conducting a Kaplan–Meier analysis based on the risk score formula, and performing a multivariate COX regression analysis on the clinical factors and risk scores. Results. A total of 62 DEGs associated with CRC lymph node metastasis were obtained. Among the 20 hub genes identified via PPI, only calcium-activated chloride channel regulator 1 (CLCA1) expression was down-regulated in lymph node metastasis, and the rest were up-regulated. A total of nine characteristic genes associated with CRC lymph node metastasis (KIF1A, TMEM59L, CLCA1, COL9A3, GDF5, TUBB2B, STMN2, FOXN1, and SCN5A) were screened using the LASSO regression method. The nine characteristic genes were significantly related to different kinds of immune cell infiltration, from which three survival-related genes (TMEM59L, CLCA1, and TUBB2B) were screened. A multi-factor COX regression showed that the risk scores obtained from TMEM59L, CLCA1, and TUBB2B were independent prognostic factors. Immunohistochemical validation was performed in tissue samples from patients with rectal and colon cancer. Conclusion. TMEM59L, CLCA1, and TUBB2B were independent prognostic factors associated with lymphatic metastasis of CRC.

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Section: Discussionmentioning

confidence: 99%

An Analysis of the Gene Expression Associated with Lymph Node Metastasis in Colorectal Cancer

Yang,

Liu,

Jiang

et al. 2023

International Journal of Genomics

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“…To probe the utility of the new set of cell surface markers to phenotype altered TEC scaffolds, we next analysed the composition of the thymic epithelia in FOXN1 Δ505/WT mice which express a dominant negative mutation of FOXN1 and consequently show substantial defects in TEC differentiation (Rota et al, 2021). A previous scRNAseq-based analysis of these animals revealed a relative enrichment of perinatal and mature cTEC against a reduction of tuft-like mTEC whereas the frequency of intertypical TEC remained unchanged.…”

Section: Discussionmentioning

confidence: 99%

“…Mice heterozygous for a Foxn1 allele with a single nucleotide loss at position 1470 (designated FOXN1 Δ505/WT ) were generated at the Genome Engineering Facility of the MRC Weatherall Institute of Molecular Medicine, University of Oxford as previously described (Rota et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells

Klein

Veiga-Villauriz

Boersch

et al. 2022

Preprint

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The network of thymic stromal cells provides essential niches with unique molecular cues controlling T-cell development and selection. Recent single-cell RNA-sequencing studies uncovered a large transcriptional heterogeneity among thymic epithelial cells (TEC) demonstrating a previously unappreciated complexity. However, there are only very few cell markers that allow a comparable phenotypic identification of TEC. Here we deconvoluted by massively parallel flow cytometry and machine learning known and novel TEC phenotypes into novel subpopulations and related these by CITEseq to the corresponding TEC subtypes defined by the cells’ individual RNA profiles. This approach phenotypically identified perinatal cTEC, physically located these cells within the cortical stromal scaffold, displayed their dynamic change during the life course and revealed their exceptional efficiency in positively selecting immature thymocytes. Collectively, we have identified novel markers that allow for an unprecedented dissection of the thymus stromal complexity, the cells physical isolation and assignment of specific functions to individual TEC subpopulations.

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“…Devoted functional studies elucidated the mechanism by which this and other C-terminal mutants exert a dominant-negative effect on wild-type FOXN1. 191 The broad spectrum of mechanism by which monoallelic FOXN1 variants lead to different degrees of thymic hypoplasia has been recently studied by Moses et al in 35 selected FOXN1 variants that were tested with transcriptional reporter assays, imaging studies, and reaggregate thymus organ cultures. This approach allowed to categorize the variants into benign, loss-or gain-of-function, and/or dominant-negatives.…”

Section: Consequences Of Thymic Hypofunctionmentioning

confidence: 99%

“…Finally a recent study identified three individuals with the same FOXN1 c.1370delA frameshift mutation. Devoted functional studies elucidated the mechanism by which this and other C‐terminal mutants exert a dominant‐negative effect on wild‐type FOXN1 191 . The broad spectrum of mechanism by which monoallelic FOXN1 variants lead to different degrees of thymic hypoplasia has been recently studied by Moses et al.…”

Section: Primary Thymic Defectsmentioning

confidence: 99%

Primary and secondary defects of the thymus

Dinges,

Amini,

Notarangelo

et al. 2024

Immunological Reviews

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SummaryThe thymus is the primary site of T‐cell development, enabling generation, and selection of a diverse repertoire of T cells that recognize non‐self, whilst remaining tolerant to self‐ antigens. Severe congenital disorders of thymic development (athymia) can be fatal if left untreated due to infections, and thymic tissue implantation is the only cure. While newborn screening for severe combined immune deficiency has allowed improved detection at birth of congenital athymia, thymic disorders acquired later in life are still underrecognized and assessing the quality of thymic function in such conditions remains a challenge. The thymus is sensitive to injury elicited from a variety of endogenous and exogenous factors, and its self‐renewal capacity decreases with age. Secondary and age‐related forms of thymic dysfunction may lead to an increased risk of infections, malignancy, and autoimmunity. Promising results have been obtained in preclinical models and clinical trials upon administration of soluble factors promoting thymic regeneration, but to date no therapy is approved for clinical use. In this review we provide a background on thymus development, function, and age‐related involution. We discuss disease mechanisms, diagnostic, and therapeutic approaches for primary and secondary thymic defects.

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FOXN1 forms higher-order nuclear condensates displaced by mutations causing immunodeficiency

Abstract: A dominant transcription factor mutation disrupting nuclear liquid phase separation causes human immunodeficiency.

Cited by 15 publications

References 78 publications

An Analysis of the Gene Expression Associated with Lymph Node Metastasis in Colorectal Cancer

An Analysis of the Gene Expression Associated with Lymph Node Metastasis in Colorectal Cancer

Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells

Primary and secondary defects of the thymus

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