Lnc-ing Trained Immunity to Chromatin Architecture

Human innate immune cells exposed to certain infections or stimuli develop enhanced immune responses upon re-infection with a different second stimulus, a process termed trained immunity. Recent studies have revealed that hematopoietic stem cells (HSCs) are integral to trained immune responses as they are able to “remember” transcriptional responses and transmit this state to their progeny to educate them how to respond to future infections. The macrophages that arise from trained HSCs are epigenetically reprogrammed and as a result robustly express immune genes, enhancing their capability to resolve infection. Accumulation of H3K4me3 epigenetic marks on multiple immune gene promoters underlie robust transcriptional responses during trained immune responses. However, the mechanism underpinning how these epigenetic marks accumulate at discrete immune gene loci has been poorly understood. In this review, we discuss the previously unexplored contributions of nuclear architecture and long non-coding RNAs on H3K4me3 promoter priming in trained immunity. Altering the activity of these lncRNAs presents a promising therapeutic approach to achieve immunomodulation in inflammatory disease states

The interaction of focal adhesion kinase with apoptotic regulators underpins anoikis resistance in human oesophageal carcinoma

Aberrant communication between survival signalling- and cell death pathways enables tumour cells to resist anoikis - the subset of apoptosis triggered by loss of cell-extracellular matrix (ECM) contact. Focal adhesion kinase (FAK) has been implicated as the key intermediate in the acquisition of anoikis resistance, as constitutively active FAK rescues epithelial cells from anoikis. Pertinent to anoikis-related regulation, enhanced FAK-dependent signalling has been demonstrated to repress p53- and Fas-mediated apoptosis. Elevated expression of FAK correlates with increased metastasis of human oesophageal squamous cell carcinoma (HOSCC). Furthermore, downregulation of Fas as well as a loss of p53 tumour suppressor function are early events in HOSCC progression. In this study, staurosporine (STS) was used to experimentally induce apoptosis in HOSCC cell lines harbouring either wild type (wt) or mutant (mt) p53-R175H. Dephosphorylation of FAK accompanied STS-mediated FAK cleavage and caspase-3 activation in the wt p53 cell lines. Consistent with the lack of FAK cleavage observed post STS treatment, the mt p53-R175H cell line displayed sustained FAK Tyr397 phosphorylation and persistent integrin β1-activated FAK. However, although the survival signals transduced by integrin-activated FAK are attributed to protein kinase B (PKB) activation, fibronectin-mediated protection to STS-mediated detachment demonstrated in the wt p53 cells lines was independent of pPKB Ser473 phosphorylation. Moreover, the altered regulation of FAK in the mt p53-R175H cell line is not due to the inability of mt p53-R175H to associate with FAK. Constitutive activation of FAK has been previously shown to protect cells from anoikis-mediated activation of caspase-8. Correspondingly, in the mt p53-R175H cell line, delayed caspase-8 activation was accompanied by the maintenance of FAK Tyr397 phosphorylation, integrin β1-associated FAK and a Fas/FAK complex. Thus, the data presented highlight that, by interacting with both major apoptotic regulators, FAK is central to anoikis-related regulation. Moreover, through maintained FAK phosphorylation, the “hot spot” mt p53-R175H may have a significant impact on the survival of tumor cells post cell detachment, by opposing the induction of anoikis

The lncRNA Connection Between Cellular Metabolism and Epigenetics in Trained Immunity

Trained immunity describes the ability of innate immune cells to form immunological memories of prior encounters with pathogens. Recollection of these memories during a secondary encounter manifests a broadly enhanced inflammatory response characterized by the increased transcription of innate immune genes. Despite this phenomenon having been described over a decade ago, our understanding of the molecular mechanisms responsible for this phenotype is still incomplete. Here we present an overview of the molecular events that lead to training. For the first time, we highlight the mechanistic role of a novel class of long non-coding RNAs (lncRNAs) in the establishment and maintenance of discrete, long lasting epigenetic modifications that are causal to the trained immune response. This recent insight fills in significant gaps in our understanding of trained immunity and reveals novel ways to exploit trained immunity for therapeutic purposes

Advances in understanding molecular regulation of innate immune memory

© 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).The epigenetic and functional reprogramming of immune genes during induction of trained immunity is accompanied by the metabolic rewiring of cellular state. This memory is induced in the hematopoietic niche and propagated to daughter cells, generating epigenetically and metabolically reprogrammed innate immune cells that are greatly enhanced in their capacity to resolve inflammation. In particular, these cells show accumulation of H3K4me3 and H3K27Ac epigenetic marks on multiple immune gene promoters and associated enhancers. However, the mechanism governing how these epigenetic marks accumulate at discrete immune gene loci has been poorly understood, until now. Here, we discuss some recent advances in the regulation of trained immunity, with a particular focus on the mechanistic role of a novel class of long non-coding RNAs in the establishment of epigenetic marks on trained immune gene promoters.M.G.N. was supported by a Spinoza Grant of the Netherlands Organization for Scientific Research. L.A.B.J. was supported by a Competitiveness Operational Program grant of the Romanian Ministry of European Funds (HINT, ID P_37_762; MySMIS 103587). M.M.M. research is supported by a Department of Science and Technology Centre of Competence Grant, an SA Medical Research Council SHIP grant, and a CSIR Parliamentary Grant, all to M.M.M, and M.M.M. is a Chan Zuckerberg Investigator of the Chan Zuckerberg Initiative.info:eu-repo/semantics/publishedVersio

Genetic regulators of cytokine responses upon BCG vaccination in children from West Africa

Genetic variation is a key factor influencing cytokine production capacity, but which genetic loci regulate cytokine production before and after vaccination, particularly in African population is unknown. Here, we aimed to identify single-nucleotide polymorphisms (SNPs) controlling cytokine responses (cQTLs) after microbial stimulation in infants of West-African ancestry, comprising of low-birth-weight neonates randomized to bacillus Calmette–Guérin (BCG) vaccine-at-birth (intervention) or to the usual delayed BCG (control). Genome-wide cytokine QTL mapping revealed 12 independent cQTLs loci, of which the LINC01082-LINC00917 locus influenced more than half of the cytokine-stimulation pairs assessed. Furthermore, nine distinct cQTLs were found among infants randomized to BCG. Functional validation confirmed that several complement genes affect cytokine response after BCG vaccination. We observed a limited overlap of common cQTLs between the West-African infants and cohorts of Western European individuals. These data reveal strong population-specific genetic effects on cytokine production and may indicate new opportunities for therapeutic intervention and vaccine development in African populations.</p

Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments

International audienc

Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments

Accumulation of trimethylation of histone H3 at lysine 4 (H3K4me3) on immune-related gene promoters underlies robust transcription during trained immunity. However, the molecular basis for this remains unknown. Here we show three-dimensional chromatin topology enables immune genes to engage in chromosomal contacts with a subset of long noncoding RNAs (lncRNAs) we have defined as immune gene-priming lncRNAs (IPLs). We show that the prototypical IPL, UMLILO, acts in cis to direct the WD repeat-containing protein 5 (WDR5)-mixed lineage leukemia protein 1 (MLL1) complex across the chemokine promoters, facilitating their H3K4me3 epigenetic priming. This mechanism is shared amongst several trained immune genes. Training mediated by β-glucan epigenetically reprograms immune genes by upregulating IPLs in manner dependent on nuclear factor of activated T cells. The murine chemokine topologically associating domain lacks an IPL, and the Cxcl genes are not trained. Strikingly, the insertion of UMLILO into the chemokine topologically associating domain in mouse macrophages resulted in training of Cxcl genes. This provides strong evidence that lncRNA-mediated regulation is central to the establishment of trained immunity