TY - JOUR A1 - Baptista, Marisa A.P. A1 - Keszei, Marton A1 - Oliveira, Mariana A1 - Sunahara, Karen K.S. A1 - Andersson, John A1 - Dahlberg, Carin I.M. A1 - Worth, Austen J. A1 - Liedén, Agne A1 - Kuo, I-Chun A1 - Wallin, Robert P.A. A1 - Snapper, Scott B. A1 - Eidsmo, Liv A1 - Scheynius, Annika A1 - Karlsson, Mikael C.I. A1 - Bouma, Gerben A1 - Burns, Siobhan O. A1 - Forsell, Mattias N.E. A1 - Thrasher, Adrian J. A1 - Nylén, Susanne A1 - Westerberg, Lisa S. T1 - Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells JF - Nature Communications N2 - Wiskott–Aldrich syndrome (WAS) is caused by loss-of-function mutations in theWASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8þ T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFNg-producing CD8þ T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8þ T cells at the expense of CD4þ T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8þ T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells. KW - Cell signalling KW - Dendritic cells KW - Disease genetics Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165966 VL - 7 ER - TY - JOUR A1 - Kuznetsov, Nikolai V. A1 - Almuzzaini, Bader A1 - Kritikou, Joanna S. A1 - Baptista, Marisa A. P. A1 - Oliveira, Mariana M. S. A1 - Keszei, Marton A1 - Snapper, Scott B. A1 - Percipalle, Piergiorgio A1 - Westerberg, Lisa S. T1 - Nuclear Wiskott-Aldrich syndrome protein co-regulates T cell factor 1-mediated transcription in T cells JF - Genome Medicine N2 - Background The Wiskott–Aldrich syndrome protein (WASp) family of actin-nucleating factors are present in the cytoplasm and in the nucleus. The role of nuclear WASp for T cell development remains incompletely defined. Methods We performed WASp chromatin immunoprecipitation and deep sequencing (ChIP-seq) in thymocytes and spleen CD4\(^+\) T cells. Results WASp was enriched at genic and intergenic regions and associated with the transcription start sites of protein-coding genes. Thymocytes and spleen CD4\(^+\) T cells showed 15 common WASp-interacting genes, including the gene encoding T cell factor (TCF)12. WASp KO thymocytes had reduced nuclear TCF12 whereas thymocytes expressing constitutively active WASp\(^{L272P}\) and WASp\(^{I296T}\) had increased nuclear TCF12, suggesting that regulated WASp activity controlled nuclear TCF12. We identify a putative DNA element enriched in WASp ChIP-seq samples identical to a TCF1-binding site and we show that WASp directly interacted with TCF1 in the nucleus. Conclusions These data place nuclear WASp in proximity with TCF1 and TCF12, essential factors for T cell development. KW - Medicine KW - WASp KW - T cells KW - ChIP-seq KW - Wiskott-Aldrich syndrome KW - TCF1 KW - TCF12 KW - Nucleus Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173486 VL - 9 ER - TY - JOUR A1 - Hennig, Thomas A1 - Michalski, Marco A1 - Rutkowski, Andrzej J. A1 - Djakovic, Lara A1 - Whisnant, Adam W. A1 - Friedl, Marie-Sophie A1 - Jha, Bhaskar Anand A1 - Baptista, Marisa A. P. A1 - L'Hernault, Anne A1 - Erhard, Florian A1 - Dölken, Lars A1 - Friedel, Caroline C. T1 - HSV-1-induced disruption of transcription termination resembles a cellular stress response but selectively increases chromatin accessibility downstream of genes JF - PLoS Pathogens N2 - Lytic herpes simplex virus 1 (HSV-1) infection triggers disruption of transcription termination (DoTT) of most cellular genes, resulting in extensive intergenic transcription. Similarly, cellular stress responses lead to gene-specific transcription downstream of genes (DoG). In this study, we performed a detailed comparison of DoTT/DoG transcription between HSV-1 infection, salt and heat stress in primary human fibroblasts using 4sU-seq and ATAC-seq. Although DoTT at late times of HSV-1 infection was substantially more prominent than DoG transcription in salt and heat stress, poly(A) read-through due to DoTT/DoG transcription and affected genes were significantly correlated between all three conditions, in particular at earlier times of infection. We speculate that HSV-1 either directly usurps a cellular stress response or disrupts the transcription termination machinery in other ways but with similar consequences. In contrast to previous reports, we found that inhibition of Ca\(^{2+}\) signaling by BAPTA-AM did not specifically inhibit DoG transcription but globally impaired transcription. Most importantly, HSV-1-induced DoTT, but not stress-induced DoG transcription, was accompanied by a strong increase in open chromatin downstream of the affected poly(A) sites. In its extent and kinetics, downstream open chromatin essentially matched the poly(A) read-through transcription. We show that this does not cause but rather requires DoTT as well as high levels of transcription into the genomic regions downstream of genes. This raises intriguing new questions regarding the role of histone repositioning in the wake of RNA Polymerase II passage downstream of impaired poly(A) site recognition. KW - DNA transcription KW - dogs KW - thermal stresses KW - chromatin KW - histones KW - gene expression KW - cellular stress responses KW - transcriptional termination Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176350 VL - 14 IS - 3 ER -