The histone methyltransferase Ezh2 restrains macrophage inflammatory responses

From Wiley via Jisc Publications RouterHistory: received 2021-02-16, rev-recd 2021-07-06, accepted 2021-07-23, pub-electronic 2021-08-31, pub-print 2021-10Article version: VoRPublication status: PublishedFunder: Medical Research Council Canada (MRC); Id: http://dx.doi.org/10.13039/501100007155; Grant(s): MR/N002024/1Funder: RCUK | Medical Research Council (MRC); Id: http://dx.doi.org/10.13039/501100000265; Grant(s): MRNO2995X/1Funder: Wellcome Trust (Wellcome); Id: http://dx.doi.org/10.13039/100010269; Grant(s): 107849/Z/15/Z, 107851/Z/15/ZFunder: RCUK | Biotechnology and Biological Sciences Research Council (BBSRC); Id: http://dx.doi.org/10.13039/501100000268; Grant(s): BB/L000954/1, BB/K003097/1Abstract: Robust inflammatory responses are critical to survival following respiratory infection, with current attention focused on the clinical consequences of the Coronavirus pandemic. Epigenetic factors are increasingly recognized as important determinants of immune responses, and EZH2 is a prominent target due to the availability of highly specific and efficacious antagonists. However, very little is known about the role of EZH2 in the myeloid lineage. Here, we show EZH2 acts in macrophages to limit inflammatory responses to activation, and in neutrophils for chemotaxis. Selective genetic deletion in macrophages results in a remarkable gain in protection from infection with the prevalent lung pathogen, pneumococcus. In contrast, neutrophils lacking EZH2 showed impaired mobility in response to chemotactic signals, and resulted in increased susceptibility to pneumococcus. In summary, EZH2 shows complex, and divergent roles in different myeloid lineages, likely contributing to the earlier conflicting reports. Compounds targeting EZH2 are likely to impair mucosal immunity; however, they may prove useful for conditions driven by pulmonary neutrophil influx, such as adult respiratory distress syndrome

POMC: The Physiological Power of Hormone Processing.

Pro-opiomelanocortin (POMC) is the archetypal polypeptide precursor of hormones and neuropeptides. In this review, we examine the variability in the individual peptides produced in different tissues and the impact of the simultaneous presence of their precursors or fragments. We also discuss the problems inherent in accurately measuring which of the precursors and their derived peptides are present in biological samples. We address how not being able to measure all the combinations of precursors and fragments quantitatively has affected our understanding of the pathophysiology associated with POMC processing. To understand how different ratios of peptides arise, we describe the role of the pro-hormone convertases (PCs) and their tissue specificities and consider the cellular processing pathways which enable regulated secretion of different peptides that play crucial roles in integrating a range of vital physiological functions. In the pituitary, correct processing of POMC peptides is essential to maintain the hypothalamic-pituitary-adrenal axis, and this processing can be disrupted in POMC-expressing tumors. In hypothalamic neurons expressing POMC, abnormalities in processing critically impact on the regulation of appetite, energy homeostasis, and body composition. More work is needed to understand whether expression of the POMC gene in a tissue equates to release of bioactive peptides. We suggest that this comprehensive view of POMC processing, with a focus on gaining a better understanding of the combination of peptides produced and their relative bioactivity, is a necessity for all involved in studying this fascinating physiological regulatory phenomenon

Maternal overnutrition programs epigenetic changes in the regulatory regions of hypothalamic Pomc in the offspring of rats.

Maternal overnutrition has been implicated in affecting the offspring by programming metabolic disorders such as obesity and diabetes, by mechanisms that are not clearly understood. This study aimed to determine the long-term impact of maternal high-fat (HF) diet feeding on epigenetic changes in the offspring's hypothalamic Pomc gene, coding a key factor in the control of energy balance. Further, it aimed to study the additional effects of postnatal overnutrition on epigenetic programming by maternal nutrition.Eight-week-old female Sprague-Dawley rats were fed HF diet or low-fat (LF) diet for 6 weeks before mating, and throughout gestation and lactation. At postnatal day 21, samples were collected from a third offspring and the remainder were weaned onto LF diet for 5 weeks, after which they were either fed LF or HF diet for 12 weeks, resulting in four groups of offspring differing by their maternal and postweaning diet.With maternal HF diet, offspring at weaning had rapid early weight gain, increased adiposity, and hyperleptinemia. The programmed adult offspring, subsequently fed LF diet, retained the increased body weight. Maternal HF diet combined with offspring HF diet caused more pronounced hyperphagia, fat mass, and insulin resistance. The ARC Pomc gene from programmed offspring at weaning showed hypermethylation in the enhancer (nPE1 and nPE2) regions and in the promoter sequence mediating leptin effects. Interestingly, hypermethylation at the Pomc promoter but not at the enhancer region persisted long term into adulthood in the programmed offspring. However, there were no additive effects on methylation levels in the regulatory regions of Pomc in programmed offspring fed a HF diet.Maternal overnutrition programs long-term epigenetic alterations in the offspring's hypothalamic Pomc promoter. This predisposes the offspring to metabolic disorders later in life

Rôle des co-régulateurs PGC-1ß et TIF2 dans la fonction du muscle squelettique chez la souris

Le muscle squelettique (MS) est un tissu métabolique important. L'objectif de ma thèse était de caractériser le rôle des corégulateurs de la transcription, PGC-1β (transcriptional coactivator peroxisome proliferator-activated receptor-gammacoactivator 1beta) et TIF2 (Transcriptional Intermediary Factor 2) dans ce tissu. Mon travail a démontré que PGC-1β limite le stress oxydatif est crucial dans le maintien de la structure et de la fonction mitochondriale, via le contrôle de l’expression de gènes impliqués dans les voies de signalisation liées à l’énergie, à la dynamique mitochondriale et à la machinerie d’import mais n'est pas indispensable pour le contenu mitochondrial. Mon travail aussi démontré que TIF2 de la MS a un impact négatif sur la durée de vie des mammifères. De plus, la déplétion de TIF2 conduit à une protection partielle du MS contre les dommages oxydatifs induits par le stress. Ainsi notre travail représente une avancée dans l’établissement futur de traitements contre les troubles liés au stress oxydatif et au vieillissement.Skeletal muscle (SM) accounting for ~ 40% of total body mass is an important metabolic tissue. The aim of my thesis was to characterize the role of transcriptional coregulators, peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) and transcriptional intermediary factor 2 (TIF2) in this tissue. My work demonstrated that PGC-1β is crucial to maintain SM mitochondrial structure and function, by controlling expression of genes involved in energy pathways, mitochondrial dynamics and import machinery, but is dispensable for mitochondrial content and fiber type maintenance. Furthermore, it limits oxidative stress. The second part of my work demonstrated that myofiber TIF2 has negative impact onmammalian life span. Moreover, TIF2 ablation leads to partial protection of SM from oxidative stress-induced damage. In conclusion, our work provides a better understanding of SM homeostasis regulation and insights in treatments for disordersrelated to oxidative stress and aging

Rôle des co-régulateurs PGC-1ß et TIF2 dans la fonction du muscle squelettique chez la souris

Le muscle squelettique (MS) est un tissu métabolique important. L'objectif de ma thèse était de caractériser le rôle des corégulateurs de la transcription, PGC-1β (transcriptional coactivator peroxisome proliferator-activated receptor-gammacoactivator 1beta) et TIF2 (Transcriptional Intermediary Factor 2) dans ce tissu. Mon travail a démontré que PGC-1β limite le stress oxydatif est crucial dans le maintien de la structure et de la fonction mitochondriale, via le contrôle de l’expression de gènes impliqués dans les voies de signalisation liées à l’énergie, à la dynamique mitochondriale et à la machinerie d’import mais n'est pas indispensable pour le contenu mitochondrial. Mon travail aussi démontré que TIF2 de la MS a un impact négatif sur la durée de vie des mammifères. De plus, la déplétion de TIF2 conduit à une protection partielle du MS contre les dommages oxydatifs induits par le stress. Ainsi notre travail représente une avancée dans l’établissement futur de traitements contre les troubles liés au stress oxydatif et au vieillissement.Skeletal muscle (SM) accounting for ~ 40% of total body mass is an important metabolic tissue. The aim of my thesis was to characterize the role of transcriptional coregulators, peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) and transcriptional intermediary factor 2 (TIF2) in this tissue. My work demonstrated that PGC-1β is crucial to maintain SM mitochondrial structure and function, by controlling expression of genes involved in energy pathways, mitochondrial dynamics and import machinery, but is dispensable for mitochondrial content and fiber type maintenance. Furthermore, it limits oxidative stress. The second part of my work demonstrated that myofiber TIF2 has negative impact onmammalian life span. Moreover, TIF2 ablation leads to partial protection of SM from oxidative stress-induced damage. In conclusion, our work provides a better understanding of SM homeostasis regulation and insights in treatments for disordersrelated to oxidative stress and aging

POMC: The Physiological Power of Hormone Processing.

Pro-opiomelanocortin (POMC) is the archetypal polypeptide precursor of hormones and neuropeptides. In this review, we examine the variability in the individual peptides produced in different tissues and the impact of the simultaneous presence of their precursors or fragments. We also discuss the problems inherent in accurately measuring which of the precursors and their derived peptides are present in biological samples. We address how not being able to measure all the combinations of precursors and fragments quantitatively has affected our understanding of the pathophysiology associated with POMC processing. To understand how different ratios of peptides arise, we describe the role of the pro-hormone convertases (PCs) and their tissue specificities and consider the cellular processing pathways which enable regulated secretion of different peptides that play crucial roles in integrating a range of vital physiological functions. In the pituitary, correct processing of POMC peptides is essential to maintain the hypothalamic-pituitary-adrenal axis, and this processing can be disrupted in POMC-expressing tumors. In hypothalamic neurons expressing POMC, abnormalities in processing critically impact on the regulation of appetite, energy homeostasis, and body composition. More work is needed to understand whether expression of the POMC gene in a tissue equates to release of bioactive peptides. We suggest that this comprehensive view of POMC processing, with a focus on gaining a better understanding of the combination of peptides produced and their relative bioactivity, is a necessity for all involved in studying this fascinating physiological regulatory phenomenon

Developmental programming of hypothalamic neuronal circuits:impact on energy balance control

The prevalence of obesity in adults and children has increased globally at an alarming rate. Mounting evidence from both epidemiological studies and animal models indicates that adult obesity and associated metabolic disorders can be programmed by intrauterine and early postnatal environment- a phenomenon known as fetal programming of adult disease. Data from nutritional intervention studies in animals including maternal under- and over-nutrition support the developmental origins of obesity and metabolic syndrome. The hypothalamic neuronal circuits located in the arcuate nucleus controlling appetite and energy expenditure are set early in life and are perturbed by maternal nutritional insults. In this review, we focus on the effects of maternal nutrition in programming permanent changes in these hypothalamic circuits, with experimental evidence from animal models of maternal under- and over-nutrition. We discuss the epigenetic modifications which regulate hypothalamic gene expression as potential molecular mechanisms linking maternal diet during pregnancy to the offspring’s risk of obesity at a later age. Understanding these mechanisms in key metabolic genes may provide insights into the development of preventative intervention strategies

A Vitamin D Receptor Selectively Activated by Gemini Analogs Reveals Ligand Dependent and Independent Effects

The bioactive form of vitamin D [1,25(OH)2D3] regulates mineral and bone homeostasis and exerts potent anti-inflammatory and antiproliferative properties through binding to the vitamin D receptor (VDR). The 3D structures of the VDR ligand-binding domain with 1,25(OH)2D3 or gemini analogs unveiled the molecular mechanism underlying ligand recognition. On the basis of structure-function correlations, we generated a point-mutated VDR (VDRgem) that is unresponsive to 1,25(OH)2D3, but the activity of which is efficiently induced by the gemini ligands. Moreover, we show that many VDR target genes are repressed by unliganded VDRgem and that mineral ion and bone homeostasis are more impaired in VDRgem mice than in VDR null mice, demonstrating that mutations abolishing VDR ligand binding result in more severe skeletal defects than VDR null mutations. As gemini ligands induce VDRgem transcriptional activity in mice and normalize their serum calcium levels, VDRgem is a powerful tool to further unravel both liganded and unliganded VDR signaling