Type 1 conventional dendritic cell fate and function are controlled by DC-SCRIPT

2021 ◽  
Vol 6 (58) ◽  
pp. eabf4432
Author(s):  
Shengbo Zhang ◽  
Hannah D. Coughlan ◽  
Mitra Ashayeripanah ◽  
Simona Seizova ◽  
Andrew J. Kueh ◽  
...  
Keyword(s):  
Cell Fate ◽  
Genetic Basis ◽  
Signature Genes ◽  
Genome Wide ◽  
Gene Expression Analyses ◽  
Plasmacytoid Dcs ◽  
Gene Regulatory ◽  
And Function ◽  
Lineage Diversity

The functional diversification of dendritic cells (DCs) is a key step in establishing protective immune responses. Despite the importance of DC lineage diversity, its genetic basis is not fully understood. The transcription factor DC-SCRIPT is expressed in conventional DCs (cDCs) and their committed bone marrow progenitors but not in plasmacytoid DCs (pDCs). We show that mice lacking DC-SCRIPT displayed substantially impaired development of IRF8 (interferon regulatory factor 8)–dependent cDC1, whereas cDC2 numbers increased marginally. The residual DC-SCRIPT–deficient cDC1s had impaired capacity to capture and present cell-associated antigens and to secrete IL-12p40, two functional hallmarks of this population. Genome-wide mapping of DC-SCRIPT binding and gene expression analyses revealed a key role for DC-SCRIPT in maintaining cDC1 identity via the direct regulation of cDC1 signature genes, including Irf8. Our study reveals DC-SCRIPT to be a critical component of the gene regulatory program shaping the functional attributes of cDC1s.

scholarly journals Gene regulatory networks in neural cell fate acquisition from genome-wide chromatin association of Geminin and Zic1

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Savita Sankar ◽  
Dhananjay Yellajoshyula ◽  
Bo Zhang ◽  
Bryan Teets ◽  
Nicole Rockweiler ◽  
...  
Keyword(s):  
Cell Fate ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Neural Cell ◽  
Genome Wide ◽  
Gene Regulatory ◽  
Neural Cell Fate

scholarly journals Specification of diverse cell types during early neurogenesis of the mouse cerebellum

2018 ◽  
Author(s):  
John W. Wizeman ◽  
Qiuxia Guo ◽  
Elliot Wilion ◽  
James Y.H. Li
Keyword(s):  
Cell Fate ◽  
Developmental Trajectories ◽  
Ventricular Zone ◽  
Cell Types ◽  
Genome Wide ◽  
Integral Role ◽  
Cerebellar Cell ◽  
Early Neurogenesis ◽  
And Function ◽  
Developing Cerebellum

SUMMARYWe applied single-cell RNA sequencing to profile genome-wide gene expression in about 9,400 individual cerebellar cells from the mouse embryo at embryonic day 13.5. Reiterative clustering identified the major cerebellar cell types and subpopulations of different lineages. Through pseudotemporal ordering to reconstruct developmental trajectories, we identified novel transcriptional programs controlling cell fate specification of populations arising from the ventricular zone and the anterior rhombic lip, two distinct germinal zones of the embryonic cerebellum. Together, our data revealed cell-specific markers for studying the cerebellum, important specification decisions, and a number of previously unknown subpopulations that may play an integral role in the formation and function of the cerebellum. Importantly, we identified a potential mechanism of vermis formation, which is affected by multiple congenital cerebellar defects. Our findings will facilitate new discovery by providing insights into the molecular and cell type diversity in the developing cerebellum.

scholarly journals Gene regulatory network architecture in different developmental contexts influences the genetic basis of morphological evolution

2017 ◽  
Author(s):  
Sebastian Kittelmann ◽  
Alexandra D. Buffry ◽  
Franziska A. Franke ◽  
Isabel Almudi ◽  
Marianne Yoth ◽  
...  
Keyword(s):  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Network Architecture ◽  
Regulatory Networks ◽  
Genetic Basis ◽  
Morphological Evolution ◽  
Phenotypic Change ◽  
Phenotypic Evolution ◽  
Gene Regulatory ◽  
And Function

AbstractConvergent phenotypic evolution is often caused by recurrent changes at particular nodes in the underlying gene regulatory networks (GRNs). The genes at such evolutionary ‘hotspots’ are thought to maximally affect the phenotype with minimal pleiotropic consequences. This has led to the suggestion that if a GRN is understood in sufficient detail, the path of evolution may be predictable. The repeated evolutionary loss of larval trichomes among Drosophila species is caused by the loss of shavenbaby (svb) expression. svb is also required for development of leg trichomes, but the evolutionary gain of trichomes in the ‘naked valley’ on T2 femurs in Drosophila melanogaster is caused by the loss of microRNA-92a (miR-92a) expression rather than changes in svb. We compared the expression and function of components between the larval and leg trichome GRNs to investigate why the genetic basis of trichome pattern evolution differs in these developmental contexts. We found key differences between the two networks in both the genes employed, and in the regulation and function of common genes. These differences in the GRNs reveal why mutations in svb are unlikely to contribute to leg trichome evolution and how instead miR-92a represents the key evolutionary switch in this context. Our work shows that variability in GRNs across different developmental contexts, as well as whether a morphological feature is lost versus gained, influence the nodes at which a GRN evolves to cause morphological change. Therefore, our findings have important implications for understanding the pathways and predictability of evolution.Author SummaryA major goal of biology is to identify the genetic cause of organismal diversity. Convergent evolution of traits is often caused by changes in the same genes – evolutionary ‘hotspots’. shavenbaby is a ‘hotspot’ for larval trichome loss in Drosophila, however microRNA-92a underlies the gain of leg trichomes. To understand this difference in the genetics of phenotypic evolution, we compared the expression and function of genes in the underlying regulatory networks. We found that the pathway of evolution is influenced by differences in gene regulatory network architecture in different developmental contexts, as well as by whether a trait is lost or gained. Therefore, hotspots in one context may not readily evolve in a different context. This has important implications for understanding the genetic basis of phenotypic change and the predictability of evolution.

A Genome-wide Assessment of the Genetic Basis of Type 1 Diabetes

2007 ◽  
Vol 123 ◽  
pp. S136
Author(s):  
Vincent Plagnol ◽  
◽  
David Clayton ◽  
David Dunger ◽  
Kate Downes ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Genetic Basis ◽  
Genome Wide ◽  
A Genome

scholarly journals p53 integrates host defense and cell fate during bacterial pneumonia

2013 ◽  
Vol 210 (5) ◽  
pp. 891-904 ◽  
Author(s):  
Jennifer H. Madenspacher ◽  
Kathleen M. Azzam ◽  
Kymberly M. Gowdy ◽  
Kenneth C. Malcolm ◽  
Jerry A. Nick ◽  
...  
Keyword(s):  
Cell Fate ◽  
Host Defense ◽  
Human Tumor ◽  
Human Neutrophils ◽  
Bacterial Killing ◽  
Immune Priming ◽  
Genome Wide ◽  
Environmental Agents ◽  
Transcription Factor P53

Cancer and infection are predominant causes of human mortality and derive, respectively, from inadequate genomic and host defenses against environmental agents. The transcription factor p53 plays a central role in human tumor suppression. Despite its expression in immune cells and broad responsiveness to stressors, it is virtually unknown whether p53 regulates host defense against infection. We report that the lungs of naive p53−/− mice display genome-wide induction of NF-κB response element–enriched proinflammatory genes, suggestive of type 1 immune priming. p53-null and p53 inhibitor–treated mice clear Gram-negative and -positive bacteria more effectively than controls after intrapulmonary infection. This is caused, at least in part, by cytokines produced by an expanded population of apoptosis-resistant, TLR-hyperresponsive alveolar macrophages that enhance airway neutrophilia. p53−/− neutrophils, in turn, display heightened phagocytosis, Nox-dependent oxidant generation, degranulation, and bacterial killing. p53 inhibition boosts bacterial killing by mouse neutrophils and oxidant generation by human neutrophils. Despite enhanced bacterial clearance, infected p53−/− mice suffer increased mortality associated with aggravated lung injury. p53 thus modulates host defense through regulating microbicidal function and fate of phagocytes, revealing a fundamental link between defense of genome and host during environmental insult.

scholarly journals Epigenetic inactivation of oncogenic brachyury (TBXT) by H3K27 histone demethylase controls chordoma cell survival

2018 ◽  
Author(s):  
Lucia Cottone ◽  
Edward S Hookway ◽  
Adam Cribbs ◽  
Graham Wells ◽  
Patrick Lombard ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Control Mechanisms ◽  
Rare Tumour ◽  
Mesoderm Development ◽  
Survival Pathways ◽  
Genome Wide ◽  
Notochord Cell ◽  
Oncogenic Driver ◽  
And Function

AbstractThe expression of the transcription factorbrachyury(TBXT) is normally restricted to embryonic development and its silencing after mesoderm development is epigenetically regulated. In chordoma, a rare tumour of notochordal differentiation, TBXT acts as a putative oncogene, and we hypothesised that its expression could be controlled through epigenetic inhibition. Screening of five chordoma cell lines revealed that only inhibitors of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (Jmjd3) reduceTBXTexpression and lead to cell death, findings validated in primary patient-derived culture systems. Pharmacological inhibition of KDM6 demethylases leads to genome-wide increases in repressive H3K27me3 marks, accompanied by significantly reduced TBXT expression, an effect that is phenocopied by the dual genetic inactivation ofKDM6A/Busing CRISPR/Cas9. Transcriptional profiles in response to a novel KDM6A/B inhibitor, KDOBA67, revealed downregulation of critical genes and transcription factor networks for chordoma survival pathways, whereas upregulated pathways were dominated by stress, cell cycle and pro-apoptotic response pathways.This study supports previous data showing that the function of TBXT is essential for maintaining notochord cell fate and function and provides further evidence that TBXT is an oncogenic driver in chordoma. Moreover, the data suggest that TBXT can potentially be targeted therapeutically by modulating epigenetic control mechanisms such as H3K27 demethylases.

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