When plants recognize potential opponents, invading pathogens, wound signals, or abiotic stress, they often switch to a primed state of enhanced defense. However, defense priming can also be induced ...by some natural or synthetic chemicals. In the primed state, plants respond to biotic and abiotic stress with faster and stronger activation of defense, and this is often linked to immunity and abiotic stress tolerance. This review covers recent advances in disclosing molecular mechanisms of priming. These include elevated levels of pattern-recognition receptors and dormant signaling enzymes, transcription factor HsfB1 activity, and alterations in chromatin state. They also comprise the identification of aspartyl-tRNA synthetase as a receptor of the priming activator β-aminobutyric acid. The article also illustrates the inheritance of priming, exemplifies the role of recently identified priming activators azelaic and pipecolic acid, elaborates on the similarity to defense priming in mammals, and discusses the potential of defense priming in agriculture.
Hematopoietic stem cells (HSCs) maintain life-long production of immune cells and can directly respond to infection, but sustained effects on the immune response remain unclear. We show that acute ...immune stimulation with lipopolysaccharide (LPS) induced only transient changes in HSC abundance, composition, progeny, and gene expression, but persistent alterations in accessibility of specific myeloid lineage enhancers occurred, which increased responsiveness of associated immune genes to secondary stimulation. Functionally, this was associated with increased myelopoiesis of pre-exposed HSCs and improved innate immunity against the gram-negative bacterium P. aeruginosa. The accessible myeloid enhancers were enriched for C/EBPβ targets, and C/EBPβ deletion erased the long-term inscription of LPS-induced epigenetic marks and gene expression. Thus, short-term immune signaling can induce C/EBPβ-dependent chromatin accessibility, resulting in HSC-trained immunity, during secondary infection. This establishes a mechanism for how infection history can be epigenetically inscribed in HSCs as an integral memory function of innate immunity.
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•LT-HSCs conserve epigenetic memory of previous infectious challenge•Increased transcriptional response of open myeloid enhancers to secondary stimulation•Memory improves myeloid differentiation and resistance to secondary infection•C/EBPβ is required for LPS-induced memory, but not transient inflammatory response
de Laval and colleagues show that LPS induces cryptic open chromatin regions in hematopoietic stem cells (HSCs). This is dependent on the pioneer transcription factor C/EBPβ. Upon secondary infection, pre-exposed HSCs show a more efficient response of myeloid enhancers, increasing myeloid differentiation, and better bacterial clearance and survival.
Epigenetic memory is an essential process of life that governs the inheritance of predestined functional characteristics of normal cells and the newly acquired properties of cells affected by cancer ...and other diseases from parental to progeny cells. Unraveling the molecular basis of epigenetic memory dictated by protein and RNA factors in conjunction with epigenetic marks that are erased and re-established during embryogenesis/development during the formation of somatic, stem and disease cells will have far reaching implications to our understanding of embryogenesis/development and various diseases including cancer. While there has been enormous progress made, there are still gaps in knowledge which includes, the identity of unique epigenetic memory factors (EMFs) and epigenome coding enzymes/co-factors/scaffolding proteins involved in the assembly of defined “epigenetic memorysomes” and the epigenome marks that constitute collections of gene specific epigenetic memories corresponding to specific cell types and physiological conditions. A better understanding of the molecular basis for epigenetic memory will play a central role in improving diagnostics and prognostics of disease states and aid the development of targeted therapeutics of complex diseases.
In previous work, we have developed a DNA methylation‐based epigenetic memory system that operates in Escherichia coli to detect environmental signals, trigger a phenotypic switch of the cells and ...store the information in DNA methylation. The system is based on the CcrM DNA methyltransferase and a synthetic zinc finger (ZnF4), which binds DNA in a CcrM methylation‐dependent manner and functions as a repressor for a ccrM gene expressed together with an egfp reporter gene. Here, we developed a reversible reset for this memory system by adding an increased concentration of ZnSO4 to the bacterial cultivation medium and demonstrate that one bacterial culture could be reversibly switched ON and OFF in several cycles. We show that a previously developed differential equation model of the memory system can also describe the new data. Then, we studied the long‐term stability of the ON‐state of the system over approximately 100 cell divisions showing a gradual loss of ON‐state signal starting after 4 days of cultivation that is caused by individual cells switching from an ON‐ into the OFF‐state. Over time, the methylation of the ZnF4‐binding sites is not fully maintained leading to an increased OFF switching probability of cells, because stronger binding of ZnF4 to partially demethylated operator sites leads to further reductions in the cellular concentrations of CcrM. These data will support future design to further stabilize the ON‐state and enforce the binary switching behaviour of the system. Together with the development of a reversible OFF switch, our new findings strongly increase the capabilities of bacterial epigenetic biosensors.
We improved DNA methylation‐based epigenetic memory systems in two aspects: (a) We describe an OFF‐switch allowing us to demonstrate reversible switching of bacteria containing the memory systems between ON‐ and OFF‐states several times. (b) We investigated the stability of the ON‐state, showing that with time individual bacterial cells experience an increasing probability to switch back into the OFF‐state, because of imperfect inheritance of the DNA methylation signal.
In this review we discuss how the mammalian interfollicular epidermis forms during development, maintains homeostasis, and is repaired following wounding. Recent studies have provided new insights ...into the relationship between the stem cell compartment and the differentiating cell layers; the ability of differentiated cells to dedifferentiate into stem cells; and the epigenetic memory of epidermal cells following wounding.
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•Switch between planar and perpendicular cell divisions during development.•Epidermal signalling is integrated at the cellular and supracellular levels.•Epigenetic environmental and lineage memory of wounding.
The long non-coding RNA (lncRNA) XIST establishes X chromosome inactivation (XCI) in female cells in early development and thereafter is thought to be largely dispensable. Here, we show XIST is ...continually required in adult human B cells to silence a subset of X-linked immune genes such as TLR7. XIST-dependent genes lack promoter DNA methylation and require continual XIST-dependent histone deacetylation. XIST RNA-directed proteomics and CRISPRi screen reveal distinctive somatic cell-type-specific XIST complexes and identify TRIM28 that mediates Pol II pausing at promoters of X-linked genes in B cells. Single-cell transcriptome data of female patients with either systemic lupus erythematosus or COVID-19 infection revealed XIST dysregulation, reflected by escape of XIST-dependent genes, in CD11c+ atypical memory B cells (ABCs). XIST inactivation with TLR7 agonism suffices to promote isotype-switched ABCs. These results indicate cell-type-specific diversification and function for lncRNA-protein complexes and suggest expanded roles for XIST in sex-differences in biology and medicine.
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•XIST prevents escape of X-linked genes with DNA hypomethylated promoters in B cells•XIST maintains X-inactivation through continuous deacetylation of H3K27ac•XIST ChIRP-MS and CRISPRi screen reveal a B cell-specific XIST cofactor TRIM28•XIST loss and TLR7 stimulation promotes CD11c+ atypical B cell formation
XIST restrains human atypical B cell development. A distinct XIST-associated protein complex contributes to XIST-mediated gene silencing in B cells.
Known for nearly a century but through mechanisms that remain elusive, cells retain a memory of inflammation that equips them to react quickly and broadly to diverse secondary stimuli. Using murine ...epidermal stem cells as a model, we elucidate how cells establish, maintain, and recall inflammatory memory. Specifically, we landscape and functionally interrogate temporal, dynamic changes to chromatin accessibility, histone modifications, and transcription factor binding that occur during inflammation, post-resolution, and in memory recall following injury. We unearth an essential, unifying role for the general stress-responsive transcription factor FOS, which partners with JUN and cooperates with stimulus-specific STAT3 to establish memory; JUN then remains with other homeostatic factors on memory domains, facilitating rapid FOS re-recruitment and gene re-activation upon diverse secondary challenges. Extending our findings, we offer a comprehensive, potentially universal mechanism behind inflammatory memory and less discriminate recall phenomena with profound implications for tissue fitness in health and disease.
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•Stimulus-specific STAT3 and broad stress factor AP1 co-establish memory domains•Stem cell factors access open memory domains and remain bound after inflammation•FOS activates open memory domains, enabling secondary responses to diverse stimuli•AP1 mediates epigenetic inflammatory memory across cell types, stimuli, and species
Fuchs and colleagues couple high-throughput chromatin profiling with genetics to unravel the mechanisms of inflammatory memory establishment, maintenance, and recall. Stimulus-specific STAT3 and general stress factor FOS:JUN establish memory, enabling stem cell factors to access and maintain memory; upon diverse secondary challenges, FOS rapidly accesses memory domains to reactivate memory-associated transcription.
Defense priming allows plants to enhance their immune responses to subsequent pathogen challenges. Recent reports suggested that acquired resistances in parental generation can be inherited into ...descendants. Although epigenetic mechanisms are plausible tools enabling the transmission of information or phenotypic traits induced by environmental cues across generations, the mechanism for the transgenerational inheritance of defense priming in plants has yet to be elucidated. With the initial aim to elucidate an epigenetic mechanism for the defense priming in plants, we reassessed the transgenerational inheritance of plant defense, however, could not observe any evidence supporting it. By using the same dipping method with previous reports, Arabidopsis was exposed repeatedly to Pseudomonas syringae pv tomato DC3000 (Pst DC3000) during vegetative or reproductive stages. Irrespective of the developmental stages of parental plants that received pathogen infection, the descendants did not exhibit primed resistance phenotypes, defense marker gene (PR1) expression, or elevated histone acetylation within PR1 chromatin. In assays using the pressure-infiltration method for infection, we obtained the same results as above. Thus, our results suggest that the previous observations on the transgenerational inheritance of defense priming in plants should be more extensively and carefully reassessed. BMB Reports 2022; 55(7): 342-347
Macrophages are first responders for the immune system. In this role, they have both effector functions for neutralizing pathogens and sentinel functions for alerting other immune cells of diverse ...pathologic threats, thereby initiating and coordinating a multipronged immune response. Macrophages are distributed throughout the body-they circulate in the blood, line the mucosal membranes, reside within organs, and survey the connective tissue. Several reviews have summarized their diverse roles in different physiological scenarios and in the initiation or amplification of different pathologies. In this review, we propose that both the effector and the sentinel functions of healthy macrophages rely on three hallmark properties: response specificity, context dependence, and stimulus memory. When these hallmark properties are diminished, the macrophage's biological functions are impaired, which in turn results in increased risk for immune dysregulation, manifested by immune deficiency or autoimmunity. We review the evidence and the molecular mechanisms supporting these functional hallmarks.
Epigenetic memory allows organisms to stably alter their transcriptional program in response to developmental or environmental stimuli. Such transcriptional programs are mediated by heritable ...regulation of the function of enhancers and promoters. Memory involves read–write systems that enable self-propagation and mitotic inheritance of cis-acting epigenetic marks to induce stable changes in transcription. Also, in response to environmental cues, cells can induce epigenetic transcriptional memory to poise inducible genes for faster induction in the future. Here, we discuss modes of epigenetic inheritance and the molecular basis of epigenetic transcriptional memory.
•Epigenetic transcriptional regulation allows for maintenance of stable expression states.•Epigenetic regulation requires DNA methylation, lncRNAs or histone modifications.•Transcriptional memory poises previously active genes for future expression.•Transcriptional memory requires H4K4me2, which is inherited through mitosis.•H3K4me2 during memory is different from H3K4 methylation during transcription.
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