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Project description:Naive CD4+ T lymphocytes differentiate into different effector types, including helper and regulatory cells (Th and Treg, respectively). Heritable gene expression programs that define these effector types are established during differentiation, but little is known about the epigenetic mechanisms that install and maintain these programs. Here, we use mice defective for different components of heterochromatin-dependent gene silencing to investigate the epigenetic control of CD4+ T cell plasticity. We show that, upon T cell receptor (TCR) engagement, naive and regulatory T cells defective for TRIM28 (an epigenetic adaptor for histone binding modules) or for heterochromatin protein 1 β and γ isoforms (HP1β/γ, 2 histone-binding factors involved in gene silencing) fail to effectively signal through the PI3K-AKT-mTOR axis and switch to glycolysis. While differentiation of naive TRIM28-/- T cells into cytokine-producing effector T cells is impaired, resulting in reduced induction of autoimmune colitis, TRIM28-/- regulatory T cells also fail to expand in vivo and to suppress autoimmunity effectively. Using a combination of transcriptome and chromatin immunoprecipitation-sequencing (ChIP-seq) analyses for H3K9me3, H3K9Ac, and RNA polymerase II, we show that reduced effector differentiation correlates with impaired transcriptional silencing at distal regulatory regions of a defined set of Treg-associated genes, including, for example, NRP1 or Snai3. We conclude that TRIM28 and HP1β/γ control metabolic reprograming through epigenetic silencing of a defined set of Treg-characteristic genes, thus allowing effective T cell expansion and differentiation into helper and regulatory phenotypes.
| S-EPMC6925996 | biostudies-literature
Project description:Critical role for TRIM28 and HP1beta/gamma in the epigenetic control of T cell metabolic reprograming and effector differentiation
| PRJNA589759 | ENA
Project description:The efficiency of remyelination decreases with age, but the molecular mechanisms responsible for this decline remain only partially understood. In this study, we show that remyelination is regulated by age-dependent epigenetic control of gene expression. In demyelinated young brains, new myelin synthesis is preceded by downregulation of oligodendrocyte differentiation inhibitors and neural stem cell markers, and this is associated with recruitment of histone deacetylases (HDACs) to promoter regions. In demyelinated old brains, HDAC recruitment is inefficient, and this allows the accumulation of transcriptional inhibitors and prevents the subsequent surge in myelin gene expression. Defective remyelination can be recapitulated in vivo in mice receiving systemic administration of pharmacological HDAC inhibitors during cuprizone treatment and is consistent with in vitro results showing defective differentiation of oligodendrocyte progenitors after silencing specific HDAC isoforms. Thus, we suggest that inefficient epigenetic modulation of the oligodendrocyte differentiation program contributes to the age-dependent decline in remyelination efficiency.
| S-EPMC2656679 | biostudies-literature
Project description:Reprogramming to induced pluripotent stem cells (iPSCs) and differentiation of pluripotent stem cells (PSCs) are regulated by epigenetic machinery. Tripartite motif protein 28 (TRIM28), a universal mediator of Krüppel-associated box domain zinc fingers (KRAB-ZNFs), is known to regulate both processes; however, the exact mechanism and identity of participating KRAB-ZNF genes remain unknown. Here, using a reporter system, we show that TRIM28/KRAB-ZNFs alter DNA methylation patterns in addition to H3K9me3 to cause stable gene repression during reprogramming. Using several expression datasets, we identified KRAB-ZNFs (ZNF114, ZNF483, ZNF589) in the human genome that maintain pluripotency. Moreover, we identified target genes repressed by these KRAB-ZNFs. Mechanistically, we demonstrated that these KRAB-ZNFs directly alter gene expression of important developmental genes by modulating H3K9me3 and DNA methylation of their promoters. In summary, TRIM28 employs KRAB-ZNFs to evoke epigenetic silencing of its target differentiation genes via H3K9me3 and DNA methylation.
| S-EPMC5785758 | biostudies-literature
Project description:A plethora of work implicates important effects of the vitamin A derivative retinoic acid (RA) in myeloid differentiation, whereas fewer studies explore the role of RA in lymphoid cells. Most work on lymphoid cells has focused on the influence of RA on CD4 T cells. Little information about the role of RA in CD8 T cell differentiation is available, and even less on cell-intrinsic effects in the CD8 T cell. This study explores the role of RA in effector and memory differentiation in a cell-intrinsic manner in the context of vaccinia virus infection. We observed the loss of the short-lived effector cell phenotype (reduced KLRG1(+), T-bet(hi), granzyme B(hi)), accompanied by an enhanced memory precursor phenotype at the effector (increased CD127(hi), IL-2(+)) and contraction phases (increased CD127(hi), IL-2(+), eomesodermin(hi)) of the CD8 response in the absence of RA signaling. The lack of RA also increased the proportion of central memory CD8s. Collectively, these results introduce a new role for RA in CD8 T cell activation and differentiation. This new role may have significant implications for optimal vaccine design in which vitamin A supplementation is used to augment effector responses, but it may be to the detriment of the long-term central memory response.
| S-EPMC3578118 | biostudies-literature
Project description:[Figure: see text].
| S-EPMC8641941 | biostudies-literature
Project description:The mitochondrial gatekeeper voltage-dependent anion channel 1 (VDAC1) controls metabolic and energy cross-talk between mitochondria and the rest of the cell and is involved in mitochondria-mediated apoptosis. Here, we compared the effects of downregulated VDAC1 expression in the U-87MG glioblastoma, MDA-MB-231 triple-negative breast cancer (TNBC), and A549 lung cancer cell lines, using small interfering RNA (siRNA) specific to human VDAC1 (si-hVDAC1). The cells were subjected to si-hVDAC1 (50 nM) treatment for 5-20 days. Although VDAC1 silencing occurred within a day, the cells underwent reprograming with respect to rewiring metabolism, elimination of cancer stem cells (CSCs), and alteration of transcription factor (TF) expression and proteins associated with differentiation, with maximal changes being observed after 3 weeks of silencing VDAC1 expression. The differentiation into fewer tumorigenic cells may be associated with the elimination of CSCs. These alterations are interconnected, as protein up- or downregulation occurred simultaneously, starting 15-20 days after VDAC1 levels were first decreased. Moreover, the VDAC1 depletion-mediated effects on a network of key regulators of cell metabolism, CSCs, TFs, and other factors leading to differentiation are coordinated and are common to the glioblastoma multiforme (GBM) and lung and breast cancer cell lines, despite differing in origin and carried mutations. Thus, our study showed that VDAC1 depletion triggers reprograming of malignant cancer cells into terminally differentiated cells and that this may be a promising therapeutic approach for various cancers.
| S-EPMC6562189 | biostudies-literature
Project description:More than one-half billion people are obese, and despite progress in genetic research, much of the heritability of obesity remains enigmatic. Here, we identify a Trim28-dependent network capable of triggering obesity in a non-Mendelian, "on/off" manner. Trim28(+/D9) mutant mice exhibit a bi-modal body-weight distribution, with isogenic animals randomly emerging as either normal or obese and few intermediates. We find that the obese-"on" state is characterized by reduced expression of an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1 and that independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype. Adipose tissue transcriptome analyses in children indicate that humans too cluster into distinct sub-populations, stratifying according to Trim28 expression, transcriptome organization, and obesity-associated imprinted gene dysregulation. These data provide evidence of discrete polyphenism in mouse and man and thus carry important implications for complex trait genetics, evolution, and medicine.
| S-EPMC4735019 | biostudies-literature
Project description:A large body of scientific evidence corroborated by clinical and animal model experiments indicates that tumor-associated macrophages (TAMs) play a crucial role in tumor development and progression. TAMs are a key immune cell type present in tumor microenvironment (TME) and associated with poor prognosis, drug resistance, enhanced angiogenesis and metastasis in cancer. TAMs are a phenotypically diverse population of myeloid cells which display tremendous plasticity and dynamic metabolic nature. A complete interpretation of pro-tumoral and anti-tumoral metabolic switch in TAMs is essential to understand immune evasion mechanisms in cancer. Recent studies have also implicated epigenetic mechanisms as significantly regulators of TAM functions. In this review we provide an overview of metabolic circuitry in TAMs, its impact on immune effector cells and interventions aimed at rewiring the metabolic circuits in TAMs. Mechanisms responsible for TAM polarization in cancer are also discussed.
| S-EPMC7475460 | biostudies-literature
Project description:Ubiquitination by serving as a major degradation signal of proteins, but also by controlling protein functioning and localization, plays critical roles in most key cellular processes. Here, we show that MITF, the master transcription factor in melanocytes, controls ubiquitination in melanoma cells. We identified FBXO32, a component of the SCF E3 ligase complex as a new MITF target gene. FBXO32 favors melanoma cell migration, proliferation, and tumor development in vivo. Transcriptomic analysis shows that FBXO32 knockdown induces a global change in melanoma gene expression profile. These include the inhibition of CDK6 in agreement with an inhibition of cell proliferation and invasion upon FBXO32 silencing. Furthermore, proteomic analysis identifies SMARC4, a component of the chromatin remodeling complexes BAF/PBAF, as a FBXO32 partner. FBXO32 and SMARCA4 co-localize at loci regulated by FBXO32, such as CDK6 suggesting that FBXO32 controls transcription through the regulation of chromatin remodeling complex activity. FBXO32 and SMARCA4 are the components of a molecular cascade, linking MITF to epigenetics, in melanoma cells.
| S-EPMC8184796 | biostudies-literature