microRNAs calibrate T cell responses by regulating mTOR.

International audienc

The developmentally regulated expression of twisted gastrulation reveals a role for bone morphogenetic proteins in the control of T cell development

The evolutionarily conserved, secreted protein Twisted gastrulation (Tsg) modulates morphogenetic effects of decapentaplegic (dpp) and its orthologs, the bone morphogenetic proteins 2 and 4 (BMP2/4), in early Drosophila and vertebrate embryos. We have uncovered a role for Tsg at a much later stage of mammalian development, during T cell differentiation in the thymus. BMP4 is expressed by thymic stroma and inhibits the proliferation of CD4(-)CD8(-) double-negative (DN) thymocytes and their differentiation to the CD4(+)CD8(+) double-positive (DP) stage in vitro. Tsg is expressed by thymocytes and up-regulated after T cell receptor signaling at two developmental checkpoints, the transition from the DN to the DP and from the DP to the CD4(+) or CD8(+) single-positive stage. Tsg can synergize with the BMP inhibitor chordin to block the BMP4-mediated inhibition of thymocyte proliferation and differentiation. These data suggest that the developmentally regulated expression of Tsg may allow thymocytes to temporarily withdraw from inhibitory BMP signals

PI3 kinase signalling blocks Foxp3 expression by sequestering Foxo factors

Expression of the regulatory T (T reg) cell–associated transcription factor Foxp3 can be induced by signals from the T cell receptor (TCR), interleukin-2 (IL-2), and transforming growth factor (TGF)-β. These signals are integrated by a network involving phosphatidylinositol 3 kinase (PI3K), protein kinase B (PKB; here referred to as Akt), and the mammalian target of rapamycin (mTOR). New studies show that the Foxo proteins Foxo1 and Foxo3a, which are inactivated by Akt, drive Foxp3 expression. These studies therefore explain the negative regulation of Foxp3 by PI3K signaling, and add Foxo proteins to the growing list of nuclear factors capable of modulating Foxp3 expression

Brain deposition of gadobutrol in children—a cross-sectional and longitudinal MRI T1 mapping study

Objectives:Depositions of linear gadolinium-based MRI contrast agents are readily visible in T1-weighted MRIs of certain brain regions in both adults and children. Macrocyclic contrast agents such as gadobutrol have so far escaped detection by qualitative MRI in children. This study aimed to assess whether there is evidence for deposition of gadobutrol in children using quantitative T1 mapping.Methods:This retrospective study included patients, naive to other gadolinium-based contrast agents than gadobutrol, who had received gadobutrol as part of a clinically indicated MRI. For each patient, T1 relaxation times at 3 T were measured using single-shot T1 mapping at two time points. In each of six brain regions, age-adjusted T1 relaxation times were correlated with a number of previous gadobutrol administrations. To combine interindividual, cross-sectional effects with intraindividual, longitudinal effects, both linear mixed model and generalized additive mixed model were applied.Results:One hundred four examinations of 52 children (age median 11.4, IQR 6.3–15, 26 female) with a median of 7 doses of gadobutrol in the history of their neurological or neurooncological disease were included. After correction for age and indeterminate disease-related effects to T1 time, a negative correlation of T1 time with the number of gadobutrol doses administered was observed in both mixed models in the putamen (beta − 1.65, p = .03) and globus pallidus (beta − 1.98, p = .012)Conclusions:The results indicate that in children, gadobutrol is deposited in the globus pallidus and putamen

Graves' disease presenting as pseudotumor cerebri: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pseudotumor cerebri is an entity characterized by elevated intracranial pressure with normal cerebrospinal fluid and no structural abnormalities detected on brain MRI scans. Common secondary causes include endocrine pathologies. Hyperthyroidism is very rarely associated and only three case reports have been published so far.</p> <p>Case presentation</p> <p>We report the case of a 31-year-old Luso-African woman with clinical symptoms and laboratory confirmation of Graves' disease that presented as pseudotumor cerebri.</p> <p>Conclusion</p> <p>This is a rare form of presentation of Graves' disease and a rare cause of pseudotumor cerebri. It should be remembered that hyperthyroidism is a potential cause of pseudotumor cerebri.</p

Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin

In addition to mediating sister chromatid cohesion during the cell cycle, the cohesin complex associates with CTCF and with active gene regulatory elements to form long-range interactions between its binding sites. Genome-wide chromosome conformation capture had shown that cohesin's main role in interphase genome organization is in mediating interactions within architectural chromosome compartments, rather than specifying compartments per se. However, it remains unclear how cohesin-mediated interactions contribute to the regulation of gene expression. We have found that the binding of CTCF and cohesin is highly enriched at enhancers and in particular at enhancer arrays or “super-enhancers” in mouse thymocytes. Using local and global chromosome conformation capture, we demonstrate that enhancer elements associate not just in linear sequence, but also in 3D, and that spatial enhancer clustering is facilitated by cohesin. The conditional deletion of cohesin from noncycling thymocytes preserved enhancer position, H3K27ac, H4K4me1, and enhancer transcription, but weakened interactions between enhancers. Interestingly, ∼50% of deregulated genes reside in the vicinity of enhancer elements, suggesting that cohesin regulates gene expression through spatial clustering of enhancer elements. We propose a model for cohesin-dependent gene regulation in which spatial clustering of enhancer elements acts as a unified mechanism for both enhancer-promoter “connections” and “insulation.

Drug-induced loss of imprinting revealed using bioluminescent reporters of Cdkn1c.

Genomic imprinting is an epigenetically mediated mechanism that regulates allelic expression of genes based upon parent-of-origin and provides a paradigm for studying epigenetic silencing and release. Here, bioluminescent reporters for the maternally-expressed imprinted gene Cdkn1c are used to examine the capacity of chromatin-modifying drugs to reverse paternal Cdkn1c silencing. Exposure of reporter mouse embryonic stem cells (mESCs) to 5-Azacytidine, HDAC inhibitors, BET inhibitors or GSK-J4 (KDM6A/B inhibitor) relieved repression of paternal Cdkn1c, either selectively or by inducing biallelic effects. Treatment of reporter fibroblasts with HDAC inhibitors or GSK-J4 resulted in similar paternal Cdkn1c activation, whereas BET inhibitor-induced loss of imprinting was specific to mESCs. Changes in allelic expression were generally not sustained in dividing cultures upon drug removal, indicating that the underlying epigenetic memory of silencing was maintained. In contrast, Cdkn1c de-repression by GSK-J4 was retained in both mESCs and fibroblasts following inhibitor removal, although this impact may be linked to cellular stress and DNA damage. Taken together, these data introduce bioluminescent reporter cells as tools for studying epigenetic silencing and disruption, and demonstrate that Cdkn1c imprinting requires distinct and cell-type specific chromatin features and modifying enzymes to enact and propagate a memory of silencing

T cell lineage choice and differentiation in the absence of the RNase III enzyme dicer

The ribonuclease III enzyme Dicer is essential for the processing of micro-RNAs (miRNAs) and small interfering RNAs (siRNAs) from double-stranded RNA precursors. miRNAs and siRNAs regulate chromatin structure, gene transcription, mRNA stability, and translation in a wide range of organisms. To provide a model system to explore the role of Dicer-generated RNAs in the differentiation of mammalian cells in vivo, we have generated a conditional Dicer allele. Deletion of Dicer at an early stage of T cell development compromised the survival of alphabeta lineage cells, whereas the numbers of gammadelta-expressing thymocytes were not affected. In developing thymocytes, Dicer was not required for the maintenance of transcriptional silencing at pericentromeric satellite sequences (constitutive heterochromatin), the maintenance of DNA methylation and X chromosome inactivation in female cells (facultative heterochromatin), and the stable shutdown of a developmentally regulated gene (developmentally regulated gene silencing). Most remarkably, given that one third of mammalian mRNAs are putative miRNA targets, Dicer seems to be dispensable for CD4/8 lineage commitment, a process in which epigenetic regulation of lineage choice has been well documented. Thus, although Dicer seems to be critical for the development of the early embryo, it may have limited impact on the implementation of some lineage-specific gene expression programs