Friend of Prmt1, FOP is a novel component of the nuclear SMN complex isolated using biotin affinity purification

SMN (survival motor neuron protein) complexes are essential for the biogenesis of uridine-rich small nuclear ribonucleoproteins (UsnRNPs). During the biogenesis, the SMN complexes bound to UsnRNPs are transported from the cytoplasm to the nucleus, and moved to Cajal body (bodies)/Gems (Cajal/Gems) where the SMN complexes- UsnRNPs are subjected to additional chemical modifications and dissociated to the SMN complexes and the mature UsnRNPs. Although the mature UsnRNPs are assembled into spliceosome with newly transcribed pre-mRNA in the perichromatin fibrils at the chromatin, the role of the dissociated nuclear SMN complexes remains undetermined. In this study, we identified Friend of Prmt1 (FOP; chromatin target of Prmt1, CHTOP; C1orf77) as a novel component of the nuclear SMN complexes by the biotin affinity purification, coupled with the mass spectrometry-based protein identification. FOP was associated with SMN, Gemines 2, 3, 4, 6, and 8, unrip, and fragile X mental retardation 1 protein (FMR1), as well as with U5and U6 snRNAs in the nucleus, but not with Sm proteins, Gemin5, coilin, and U1 and U2snRNAs. Using the quantitative proteomic method with SILAC coupled with RNA interference, we also showed that FOP is required for the association of the SMN complexes with hnRNPs, histone proteins, and various RNA-binding proteins. It is reported that FOP localizes mainly in the nuclear speckles, binds chromatin, and plays a role in mRNA transcriptional regulation. Our present data suggest that the nuclear SMN complex containing FOP participates in the process of mRNA post-transcriptional regulation

The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF

The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20−/− cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a wellestablished inhibitor of mTOR, also strongly protected NK-A20−/− cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis

Contribution of Intragenic DNA Methylation in Mouse Gametic DNA Methylomes to Establish Oocyte-Specific Heritable Marks

Genome-wide dynamic changes in DNA methylation are indispensable for germline development and genomic imprinting in mammals. Here, we report single-base resolution DNA methylome and transcriptome maps of mouse germ cells, generated using whole-genome shotgun bisulfite sequencing and cDNA sequencing (mRNA-seq). Oocyte genomes showed a significant positive correlation between mRNA transcript levels and methylation of the transcribed region. Sperm genomes had nearly complete coverage of methylation, except in the CpG-rich regions, and showed a significant negative correlation between gene expression and promoter methylation. Thus, these methylome maps revealed that oocytes and sperms are widely different in the extent and distribution of DNA methylation. Furthermore, a comparison of oocyte and sperm methylomes identified more than 1,600 CpG islands differentially methylated in oocytes and sperm (germline differentially methylated regions, gDMRs), in addition to the known imprinting control regions (ICRs). About half of these differentially methylated DNA sequences appear to be at least partially resistant to the global DNA demethylation that occurs during preimplantation development. In the absence of Dnmt3L, neither methylation of most oocyte-methylated gDMRs nor intragenic methylation was observed. There was also genome-wide hypomethylation, and partial methylation at particular retrotransposons, while maintaining global gene expression, in oocytes. Along with the identification of the many Dnmt3L-dependent gDMRs at intragenic regions, the present results suggest that oocyte methylation can be divided into 2 types: Dnmt3L-dependent methylation, which is required for maternal methylation imprinting, and Dnmt3L-independent methylation, which might be essential for endogenous retroviral DNA silencing. The present data provide entirely new perspectives on the evaluation of epigenetic markers in germline cells

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The transcription factor ZEB2 is required to maintain the tissue-specific identities of macrophages

Heterogeneity between different macrophage populations has become a defining feature of this lineage. However, the conserved factors defining macrophages remain largely unknown. The transcription factor ZEB2 is best described for its role in epithelial to mesenchymal transition; however, its role within the immune system is only now being elucidated. We show here that Zeb2 expression is a conserved feature of macrophages. Using Clec4f-cre, Itgax-cre, and Fcgr1-cre mice to target five different macrophage populations, we found that loss of ZEB2 resulted in macrophage disappearance from the tissues, coupled with their subsequent replenishment from bone-marrow precursors in open niches. Mechanistically, we found that ZEB2 functioned to maintain the tissue-specific identities of macrophages. In Kupffer cells, ZEB2 achieved this by regulating expression of the transcription factor LXR alpha, removal of which recapitulated the loss of Kupffer cell identity and disappearance. Thus, ZEB2 expression is required in macrophages to preserve their tissue-specific identities

L'oral dans l'éducation

La Revue internationale d’éducation de Sèvres s’intéresse, dans ce numéro 86, à la question de l’oral en éducation. Si l’on observe depuis quelques années au sein du système éducatif français une volonté de meilleure prise en compte, il était important d’observer les pratiques qui ont cours ailleurs. L’étude présente la situation dans une dizaine de pays sur quatre continents Partout, cette question de l’expression orale fait désormais partie des « compétences du XXIe siècle » et l’on se préoccupe de savoir comment parler, comment écouter. Pour autant, cette comparaison internationale permet pour la première fois de faire émerger des différences, d’une culture scolaire à une autre, d’une tradition à une autre. L’importance donnée à l’oral diffère également grandement selon les pays. Un double consensus se dégage toutefois de l’ensemble des articles : l’oral s’apprend et doit s’enseigner. Ne pas le faire, c’est contribuer au maintien ou, pire, au renforcement des inégalités entre les élèves. Autre point de large convergence : le rôle moteur de l’oral pour l’ensemble des apprentissages scolaires. Enseigner la parole, c’est donner les moyens de la prendre dans l’espace public et la vie sociale. C’est aussi l’affaire de tous et de toutes les matières. Car l’enjeu aujourd’hui n’est pas seulement d’apprendre à se servir de la parole mais aussi de se servir de la parole pour apprendre. As a legacy of various histories the spoken word is taken into account in very diverse ways. However this should not mask a broader trend, born of manifold origins, towards increasing the attention paid to written and spoken communication skills. These skills, which have often been overlooked – if not considered risky – and in any case poorly defined in schools, need to become a genuine learning object. This comparative study proposes ‘oracy’ as a concept to refer to a set of skills specific to the spoken word, including that of listening; skills which are drawn upon in order to develop various abilities to express oneself orally, to promote more democratic social participation as well as to enhance learning across the board. A pragmatic approach of oral curricula seems most beneficial, and is to be grounded in a clear vision of the relevant standards, as well as taking into account the specific issues of how to assess oracy and teacher training. La gran diversidad de la toma en cuenta de lo oral, herencia de diversas historias, no debe esconder el movimiento general, impulsado por unos motivos de orígenes múltiples, a favor de un desarrollo de la atención dedicada a lo oral. Este último, que era hasta ahora un objeto desapercibido, e incluso considerado como arriesgado, por lo menos mal definido en contexto escolar, debe convertirse en auténtico objeto de aprendizaje : esta comparación internacional propone el concepto de «oracía» («oratie») para designar un conjunto de competencias específicas para lo oral, entre las que figura la de escuchar, implementadas tanto para desarrollar ciertas capacidades de expresión oral como para desarrollar la vida social en un sentido democrático y para aprender mejor, en la totalidad de los campos. Una orientación pragmática de los currículos de lo oral debe ser favorecida, acompañándola de una visión clara de las normas retenidas, y tomando en cuenta las cuestiones específicas de evaluación de lo oral y de la formación de los docentes