The Role of ZBP-89 in Globin Regulation

The ameliorating effect of increased γ‐globin gene expression in β‐thalassemia and Sickle cell disease, favored γ‐globin gene reactivation as the most attractive treatment approach. This has led to intense research efforts to elucidate the mechanism of γ‐globin gene switching with the aim of reversing the switching process. Many DNA cis elements (e.g. LCR, ‐117 HPFH mutation, BGL3 region) as well as trans regulatory protein such as BCL11a, LDB1, and KLF1 has been identified that are important for developmental globin genes regulation. This and other evidences from literature suggest the involvement of other protein factors, as yet unknown, on γ‐globin promoter or LCR that work remotely with previously known protein factors. We recently described an unbiased proteomics approach; Targeted Chromatin Purification (TChP), to identify other possible proteins involved in γ‐globin silencing. ZBP‐89 was identified as one of the proteins in γ‐globin chromatin purification. Here we report functional study on the role of ZBP‐89 in globin regulation

Five friends of methylated chromatin target of protein-arginine- methyltransferase[Prmt]-1 (Chtop), a complex linking arginine methylation to desumoylation

Chromatin target of Prmt1 (Chtop) is a vertebrate-specific chromatin-bound protein that plays an important role in transcriptional regulation. As its mechanism of action remains unclear, we identified Chtop-interacting proteins using a biotinylation-proteomics approach. Here we describe the identification and initial characterization of Five Friends of Methylated Chtop (5FMC). 5FMC is a nuclear complex that can only be recruited by Chtop when the latter is arginine-methylated by Prmt1. It consists of the co-activator Pelp1, the Sumo-specific protease Senp3, Wdr18, Tex10, and Las1L. Pelp1 functions as the core of 5FMC, as the other components become unstable in the absence of Pelp1. We show that recruitment of 5FMC to Zbp-89, a zinc-finger transcription factor, affects its sumoylation status and transactivation potential. Collectively, our data provide a mechanistic link between arginine methylation and (de)sumoylation in the control of transcriptional activity

Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity

Item does not contain fulltextMonocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. We characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naive, tolerized, and trained macrophages. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity. beta-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in deoxyribonuclease I hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. Altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans

mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity

Contains fulltext : 133057.pdf (publisher's version ) (Closed access)Epigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles of human monocytes trained with the Candida albicans cell wall constituent beta-glucan, together with a genome-wide transcriptome, we identified the induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD(+)) to its reduced form (NADH), reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1-Akt-HIF-1alpha (hypoxia-inducible factor-1alpha) pathway. Inhibition of Akt, mTOR, or HIF-1alpha blocked monocyte induction of trained immunity, whereas the adenosine monophosphate-activated protein kinase activator metformin inhibited the innate immune response to fungal infection. Mice with a myeloid cell-specific defect in HIF-1alpha were unable to mount trained immunity against bacterial sepsis. Our results indicate that induction of aerobic glycolysis through an Akt-mTOR-HIF-1alpha pathway represents the metabolic basis of trained immunity

Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity

Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. We characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naive, tolerized, and trained macrophages. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity. beta-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in deoxyribonuclease I hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. Altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans

mTOR- and HIF-1 -mediated aerobic glycolysis as metabolic basis for trained immunity

International audienceEpigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles of human monocytes trained with the Candida albicans cell wall constituent β-glucan, together with a genome-wide transcriptome, we identified the induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD(+)) to its reduced form (NADH), reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1-Akt-HIF-1α (hypoxia-inducible factor-1α) pathway. Inhibition of Akt, mTOR, or HIF-1α blocked monocyte induction of trained immunity, whereas the adenosine monophosphate-activated protein kinase activator metformin inhibited the innate immune response to fungal infection. Mice with a myeloid cell-specific defect in HIF-1α were unable to mount trained immunity against bacterial sepsis. Our results indicate that induction of aerobic glycolysis through an Akt-mTOR-HIF-1α pathway represents the metabolic basis of trained immunity

Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity

Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. We characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naive, tolerized, and trained macrophages. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity. beta-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in deoxyribonuclease I hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. Altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans