MicroRNAs in hematopoietic development

Background: MicroRNAs (miRNAs) are short non-coding RNAs involved in the posttranscriptional regulation of a wide range of biological processes. By binding to complementary sequences on target messenger RNAs, they trigger translational repression and degradation of the target, eventually resulting in reduced protein output. MiRNA-dependent regulation of protein translation is a very widespread and evolutionarily conserved mechanism of posttranscriptional control of gene expression. Accordingly, a high proportion of mammalian genes are likely to be regulated by miRNAs. In the hematopoietic system, both transcriptional and posttranscriptional regulation of gene expression ensure proper differentiation and function of stem cells, committed progenitors as well as mature cells. Results : In recent years, miRNA expression profiling of various cell types in the hematopoietic system, as well as gene-targeting approaches to assess the function of individual miRNAs, revealed the importance of this type of regulation in the development of both innate and acquired immunity. Conclusions : We discuss the general role of miRNA biogenesis in the development of hematopoietic cells, as well as specific functions of individual miRNAs in stem cells as well as in mature immune cells

Dnmt3a restrains mast cell inflammatory responses

DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations in DNMT3A correlate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By using mast cells lacking Dnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in the absence of Dnmt3a were recapitulated or enhanced by treatment with the demethylating agent 5-aza-2′-deoxycytidine as well as by down-modulation of Dnmt1 expression, further supporting the role of DNA methylation in regulating mast cell activation. Mechanistically, these effects were in part mediated by the dysregulated expression of the scaffold protein IQGAP2, which is characterized by the ability to regulate a wide variety of biological processes. Altogether, our data demonstrate that DNMT3A and DNA methylation are key modulators of mast cell responsiveness to acute and chronic stimulation

miR-146a and NF-κB1 regulate mast cell survival and T lymphocyte differentiation

The transcription factor NF-κB regulates the expression of a broad number of genes central to immune and inflammatory responses. We identified a new molecular network that comprises specifically the NF-κB family member NF-κB1 (p50) and miR-146a, and we show that in mast cells it contributes to the regulation of cell homeostasis and survival, while in T lymphocytes it modulates T cell memory formation. Increased mast cell survival was due to unbalanced expression of pro- and antiapoptotic factors and particularly to the complete inability of p50- deleted mast cells to induce expression of miR-146a, which in the context of mast cell survival acted as a proapoptotic factor. Interestingly, in a different cellular context, namely, human and mouse primary T lymphocytes, miR-146a and NF-κB p50 did not influence cell survival or cytokine production but rather T cell expansion and activation in response to T cell receptor (TCR) engagement. Our data identify a new molecular network important in modulating adaptive and innate immune responses and show how the same activation-induced microRNA (miRNA) can be similarly regulated in different cell types even in response to different stimuli but can still determine very different outcomes, likely depending on the specific transcriptome

TET2 regulates mast cell differentiation and proliferation through catalytic and non-catalytic activities

Dioxygenases of the TET family impact genome functions by converting 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC). Here, we identified TET2 as a crucial regulator of mast cell differentiation and proliferation. In the absence of TET2, mast cells showed disrupted gene expression and altered genome-wide 5hmC deposition, especially at enhancers and in the proximity of downregulated genes. Impaired differentiation of Tet2- ablated cells could be relieved or further exacerbated by modulating the activity of other TET family members, and mechanistically it could be linked to the dysregulated expression of C/EBP family transcription factors. Conversely, the marked increase in proliferation induced by the loss of TET2 could be rescued exclusively by re-expression of wild-type or catalytically inactive TET2. Our data indicate that, in the absence of TET2, mast cell differentiation is under the control of compensatory mechanisms mediated by other TET family members, while proliferation is strictly dependent on TET2 expression

One Planet: One Health. A Call to Support the Initiative on a Global Science-Policy Body on Chemicals and Waste

The chemical pollution crisis severely threatens human and environmental health globally. To tackle this challenge the establishment of an overarching international science–policy body has recently been suggested. We strongly support this initiative based on the awareness that humanity has already likely left the safe operating space within planetary boundaries for novel entities including chemical pollution. Immediate action is essential and needs to be informed by sound scientific knowledge and data compiled and critically evaluated by an overarching science–policy interface body. Major challenges for such a body are (i) to foster global knowledge production on exposure, impacts and governance going beyond data-rich regions (e.g., Europe and North America), (ii) to cover the entirety of hazardous chemicals, mixtures and wastes, (iii) to follow a one-health perspective considering the risks posed by chemicals and waste on ecosystem and human health, and (iv) to strive for solution-oriented assessments based on systems thinking. Based on multiple evidence on urgent action on a global scale, we call scientists and practitioners to mobilize their scientific networks and to intensify science–policy interaction with national governments to support the negotiations on the establishment of an intergovernmental body based on scientific knowledge explaining the anticipated benefit for human and environmental health

La fotografia aerea e il sensore iperspettrale MIVIS per l’indagine archeologica e la ricostruzione del territorio della parte settentrionale dell’antico ducato Longobardo del Friuli

International audienceThis project has as its ultimate goal the reconstruction of the dynamics of settlement and the territory of a portion of the Region Friuli Venezia Giulia in the Lombard period. To do so, we started from the collecting of the archival documentation about excavations, surveys and past studies integrating them with the analysis of historical maps and modern technology available, as aerial photography combined with oblique aerial photography and the UAV technology, GIS and WebGIS, 3D landscape reconstruction. In particular, what concerns us here is the study of aerial photographs, the use of which in archaeology is now an established and widely used methodology for the identification and interpretation of anomalies visible onto the ground. For our work we used the aerial photographs found in the Cartographic Office of the Region, those from the MIVIS sensor found again in the same office and those found in the Central Institution for the Catalogue and the Documentation (ICCD) managing to cover an historical period from 1938 to 2007.All information derived from these analyses will be completed by the production of oblique aerial photographs and surveys by UAVs in order to identify possible anomalies which can be confirmed or refuted by the integration with the archive data

Dnmt3a restrains mast cell inflammatory responses.

DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations in DNMT3A correlate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By using mast cells lacking Dnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in the absence of Dnmt3a were recapitulated or enhanced by treatment with the demethylating agent 5-aza-2'-deoxycytidine as well as by down-modulation of Dnmt1 expression, further supporting the role of DNA methylation in regulating mast cell activation. Mechanistically, these effects were in part mediated by the dysregulated expression of the scaffold protein IQGAP2, which is characterized by the ability to regulate a wide variety of biological processes. Altogether, our data demonstrate that DNMT3A and DNA methylation are key modulators of mast cell responsiveness to acute and chronic stimulation

A molecular network regulating the proinflammatory phenotype of human memory T lymphocytes

Understanding the mechanisms that modulate helper T lymphocyte functions is crucial to decipher normal and pathogenic immune responses in humans. To identify molecular determinants influencing the pathogenicity of T cells, we separated ex vivo-isolated primary human memory T lymphocytes on the basis of their ability to produce high levels of inflammatory cytokines. We found that the inflammatory, cytokine-producing phenotype of memory T lymphocytes was defined by a specific core gene signature and was mechanistically regulated by the constitutive activation of the NF-κB pathway and by the expression of the transcriptional repressor BHLHE40. BHLHE40 attenuated the expression of anti-inflammatory factors, including miR-146a, a negative regulator of NF-κB activation and ZC3H12D, an RNase of the Regnase-1 family able to degrade inflammatory transcripts. Our data reveal a molecular network regulating the proinflammatory phenotype of human memory T lymphocytes, with the potential to contribute to disease