Talin Rod Domain Containing Protein 1 (TLNRD1) is a novel actin-bundling protein which promotes filopodia formation

Cowell, Alana R.; Jacquemet, Guillaume; Singh, Abhimanyu; Ammon, York-Christoph; Brown, David G.; Akhmanova, Anna; Ivaska, Johanna; Goult, Benjamin T.

doi:10.1101/2020.05.19.103606

Cited by 5 publications

(4 citation statements)

References 58 publications

(95 reference statements)

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“…4b ). TLNRD1 has previously been found to interact with F-actin 49,50 , similar to some other proteins known to interact with the CCM complex ( Fig. 3a ), and to regulate cell migration in a cancer cell line 49 .…”

Section: From Association To Function At 15q251mentioning

confidence: 57%

“…TLNRD1 has previously been found to interact with F-actin 49,50 , similar to some other proteins known to interact with the CCM complex ( Fig. 3a ), and to regulate cell migration in a cancer cell line 49 . However, it has not been previously linked to coronary artery disease, the CCM complex, or any function in endothelial cells.…”

Section: From Association To Function At 15q251mentioning

confidence: 57%

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Mapping the convergence of genes for coronary artery disease onto endothelial cell programs

Schnitzler

Kang

Lee-Kim

et al. 2022

Preprint

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Genome-wide association studies (GWAS) have discovered thousands of risk loci for common, complex diseases, each of which could point to genes and gene programs that influence disease. For some diseases, it has been observed that GWAS signals converge on a smaller number of biological programs, and that this convergence can help to identify causal genes. However, identifying such convergence remains challenging: each GWAS locus can have many candidate genes, each gene might act in one or more possible programs, and it remains unclear which programs might influence disease risk. Here, we developed a new approach to address this challenge, by creating unbiased maps to link disease variants to genes to programs (V2G2P) in a given cell type. We applied this approach to study the role of endothelial cells in the genetics of coronary artery disease (CAD). To link variants to genes, we constructed enhancer-gene maps using the Activity-by-Contact model. To link genes to programs, we applied CRISPRi-Perturb-seq to knock down all expressed genes within +/-500 Kb of 306 CAD GWAS signals and identify their effects on gene expression programs using single-cell RNA-sequencing. By combining these variant-to-gene and gene-to-program maps, we find that 43 of 306 CAD GWAS signals converge onto 5 gene programs linked to the cerebral cavernous malformations (CCM) pathway, which is known to coordinate transcriptional responses in endothelial cells, but has not been previously linked to CAD risk. The strongest regulator of these programs is TLNRD1, which we show is a new CAD gene and novel regulator of the CCM pathway. TLNRD1 loss-of-function alters actin organization and barrier function in endothelial cells in vitro, and heart development in zebrafish in vivo. Together, our study identifies convergence of CAD risk loci into prioritized gene programs in endothelial cells, nominates new genes of potential therapeutic relevance for CAD, and demonstrates a generalizable strategy to connect disease variants to functions.

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Section: From Association To Function At 15q251mentioning

confidence: 57%

Section: From Association To Function At 15q251mentioning

confidence: 57%

Mapping the convergence of genes for coronary artery disease onto endothelial cell programs

Schnitzler

Kang

Lee-Kim

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…5g) exhibits a shift from dim actin signal to brighter, more prominent stress fibers throughout the entire cell, with no notable change in cell shape. Given past work characterizing TLNRD1 as an actin bundler that localizes to thick stress fibers 42 , the VIEWS result suggests a role for TLNRD1 in limiting stress fiber thickness. Inspection of the LIM and SH3 domain protein 1 (LASP1, Fig.…”

Section: Precise Interpretable Visualization Of Phenotypic Shifts In ...mentioning

confidence: 77%

Mapping variation in the morphological landscape of human cells with optical pooled CRISPRi screening

Labitigan

Sanborn

Hao

et al. 2022

Preprint

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The contributions of individual genes to cell-scale morphology and cytoskeletal organization are challenging to define due to the wide intercellular variation of these complex phenotypes. We leveraged the controlled nature of image-based pooled screening to assess the impact of CRISPRi knockdown of 366 genes on cell and nuclear morphology in human U2OS osteosarcoma cells. Screen scale-up was facilitated by a new, efficient barcode readout method that successfully genotyped 85% of cells. Phenotype analysis using a deep learning algorithm, the β-variational autoencoder, produced a feature embedding space distinct from one derived from conventional morphological profiling, but detected similar gene hits while requiring minimal design decisions. We found 45 gene hits and visualized their effect by rationally constrained sampling of cells along the direction of phenotypic shift. By relating these phenotypic shifts to each other, we construct a quantitative and interpretable space of morphological variation in human cells.

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“…All the crystal structures of talin R7–R8 reported to date have shown an open conformation where there are limited contacts between the R7 and R8 subdomains 11, 38, 48 and such an interaction was not readily apparent in the NMR analysis (Fig.S4A). However, the recent crystal structure of TLNRD1 (talin rod domain containing protein 1 (PDB:6XZ4 49 ), a protein structurally homologous to talin R7–R8, revealed a similar close association of the two subdomains, supporting the notion that the two talin subdomains might also interact. One possibility is that the interaction between two domains might reduce accessibility to ligand binding sites on the domains, and perturb the localisation of the FA markers within adhesions (Fig.4B,C), affecting cell behaviour.…”

Section: Discussionmentioning

confidence: 90%

Cancer associated talin point mutations disorganise cell adhesion and migration

Azizi

Cowell

Mykuliak

et al. 2020

Preprint

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Talin-1 is a key component of the multiprotein adhesion complexes which mediate cell migration, adhesion and integrin signalling and has been linked to cancer in several studies. In this study we analysed mutations in talin-1 reported in the Catalogue of Somatic Mutations in Cancer. A total of 11 talin mutants were selected and expressed in talin-deficient fibroblasts and their functional and structural effects were characterised in detail. An I392N point mutation in the F3 domain caused a three-fold increase in invasion, and enhanced migration compared to wildtype talin. Mutations R1368W and L1539P in the R7 and R8 domains caused increased invasion and proliferation and affected talin-vinculin complexation, but were not linked to changes in their binding affinities with known substrates KANK1 and RIAM measured for isolated talin domains. Lastly, L2509P, a mutation in the dimerisation domain of talin, prevented talin dimer formation, actin recruitment and FAKpTyr397 activation leading to anisotropic cell spreading and loss of random migration. Altogether, this study suggests that cancer derived point mutations in talin-1 can drastically affect cell behaviour and so may contribute to cancer progression. , I. L. et al. (2015). Vinculin controls talin engagement with the actomyosin machinery. Nat. Commun. 6, 10038. (2017). Downregulation of Talin1 promotes hepatocellular carcinoma progression through activation of the ERK1/2 pathway. Leinonen, R., Shumway, M. et al. (2012). The 1000 genomes project: Data management and community access. Nat. Methods 9, 459-462. (2009). Stretching single talin rod molecules activates vinculin binding. Science 323, 638-641. Dupont, S., Morsut, L., Aragona, M., Enzo, E., Giulitti, S., Cordenonsi, M., Zanconato, F., Le Digabel, J., Forcato, M., Bicciato, S. et al. (2011). Role of YAP/TAZ in mechanotransduction. Nature 474, 179-183. Kim, N. G. and Gumbiner, B. M. (2015). Adhesion to fibronectin regulates hippo signaling via the FAK-src-PI3K pathway. A. R. et al. (2010). Studies on the morphology and spreading of human endothelial cells define key inter-and intramolecular interactions for talin1. Eur. J. Cell Biol. 89, 661-673. . (2016). Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity. Guichard, S. et al. (2016). Rho-associated kinase (ROCK) function is essential for cell cycle progression, senescence and tumorigenesis. Elife 5, e12994. . (2011). Talin-1 overexpression defines high risk foraggressive oral squamous cell carcinoma and promotes cancer metastasis. . (2010). Improved side-chain torsion potentials for the amber ff99SB protein force field.Proteins 78, 1950-1958.

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Talin Rod Domain Containing Protein 1 (TLNRD1) is a novel actin-bundling protein which promotes filopodia formation

Cited by 5 publications

References 58 publications

Mapping the convergence of genes for coronary artery disease onto endothelial cell programs

Mapping the convergence of genes for coronary artery disease onto endothelial cell programs

Mapping variation in the morphological landscape of human cells with optical pooled CRISPRi screening

Cancer associated talin point mutations disorganise cell adhesion and migration

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