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Polycomb proteins are critical chromatin modifiers that regulate stem cell differentiation via transcriptional repression. In skeletal muscle progenitors Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), contributes to maintain the chromatin of muscle genes in a repressive conformation, whereas its down-regulation allows the progression through the myogenic programme. Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372. Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2. Our results indicate that signal-dependent degradation of EZH2 is a prerequisite for satellite cells differentiation and identify PJA1 as a new player in the epigenetic control of muscle gene expression. In skeletal muscle progenitors, EZH2 maintains myogenic genes in a repressed state, but during differentiation its levels are reduced via unknown mechanisms. Here the authors show that during myogenesis, p38α kinase phosphorylates EZH2 and targets it for degradation by the ubiquitin ligase PRAJA1.

Inefficient targeting of muscle stem cells (MuSCs), also called satellite cells, represents a major bottleneck of current therapeutic strategies for muscular dystrophies, as it precludes the possibility of promoting compensatory regeneration. Here we describe a muscle-targeting delivery platform, based on gold nanoparticles, that enables the release of therapeutic oligonucleotides into MuSCs. We demonstrate that AuNPs conjugation to an aptamer against α7/β1 integrin dimers directs either local or systemic delivery of microRNA-206 to MuSCs, thereby promoting muscle regeneration and improving muscle functionality, in a mouse model of Duchenne Muscular Dystrophy. We show here that this platform is biocompatible, non-toxic, and non-immunogenic, and it can be easily adapted for the release of a wide range of therapeutic oligonucleotides into diseased muscles. Lack of muscle stem cell targeting limits the treatment of muscular dystrophies. Here, the authors describe a platform based on functionalized gold nanoparticles that allows selective delivery of therapeutic oligonucleotides and promotes skeletal muscle regeneration.

Autism spectrum disorder (ASD) includes a set of highly heritable neurodevelopmental syndromes characterized by social and communication impairment, repetitive behaviour, and intellectual disability. Although mutations in multiple genes have been associated to ASD, most patients lack detectable genetic alterations. For this reason, environmental factors are commonly thought to also contribute to ASD aetiology. Transcriptome analyses have revealed that autistic brains possess distinct gene expression signatures, whose elucidation can provide insights about the mechanisms underlying the effects of ASD-causing genetic and environmental factors. Herein, we have identified a coordinated and temporally regulated programme of gene expression in the post-natal development of cerebellum, a brain area whose defects are strongly associated with ASD. Notably, this cerebellar developmental programme is significantly enriched in ASD-linked genes. Clustering analyses highlighted six different patterns of gene expression modulated during cerebellar development, with most of them being enriched in functional processes that are frequently dysregulated in ASD. By using the valproic acid mouse model of ASD, we found that ASD-linked genes are dysregulated in the developing cerebellum of ASD-like mice, a defect that correlates with impaired social behaviour and altered cerebellar cortical morphology. Moreover, changes in transcript levels were reflected in aberrant protein expression, indicating the functional relevance of these alterations. Thus, our work uncovers a complex ASD-related transcriptional programme regulated during cerebellar development and highlight genes whose expression is dysregulated in this brain area of an ASD mouse model.

The field of human population mapping is constantly evolving, leveraging the increasing availability of high-resolution satellite imagery and the advancements in the field of machine learning. In recent years, the emergence of global built-area datasets that accurately describe the extent, location, and characteristics of human settlements has facilitated the production of new population grids, with improved quality, accuracy, and spatial resolution. In this research, we explore the capabilities of the novel World Settlement Footprint 2019 Imperviousness layer (WSF2019-Imp), as a single proxy in the production of a new high-resolution population distribution dataset for all of Africa—the WSF2019-Population dataset (WSF2019-Pop). Results of a comprehensive qualitative and quantitative assessment indicate that the WSF2019-Imp layer has the potential to overcome the complexities and limitations of top-down binary and multi-layer approaches of large-scale population mapping, by delivering a weighting framework which is spatially consistent and free of applicability restrictions. The increased thematic detail and spatial resolution (~10 m at the Equator) of the WSF2019-Imp layer improve the spatial distribution of populations at local scales, where fully built-up settlement pixels are clearly differentiated from settlement pixels that share a proportion of their area with green spaces, such as parks or gardens. Overall, eighty percent of the African countries reported estimation accuracies with percentage mean absolute errors between ~15% and ~32%, and 50% of the validation units in more than half of the countries reported relative errors below 20%. Here, the remaining lack of information on the vertical dimension and the functional characterisation of the built-up environment are still remaining limitations affecting the quality and accuracy of the final population datasets.

Skeletal muscle exhibits a high regenerative capacity, mainly due to the ability of satellite cells to replicate and differentiate in response to appropriate stimuli. Epigenetic control is effective at different stages of this process. It has been shown that the chromatin-remodeling factor HDAC4 is able to regulate satellite cell proliferation and commitment. However, its molecular targets are still uncovered. To explain the signaling pathways regulated by HDAC4 in satellite cells, we generated tamoxifen-inducible mice with conditional inactivation of HDAC4 in Pax7 + cells (HDAC4 KO mice). We found that the proliferation and differentiation of HDAC4 KO satellite cells were compromised, although similar amounts of satellite cells were found in mice. Moreover, we found that the inhibition of HDAC4 in satellite cells was sufficient to block the differentiation process. By RNA-sequencing analysis we identified P21 and Sharp1 as HDAC4 target genes. Reducing the expression of these target genes in HDAC4 KO satellite cells, we also defined the molecular pathways regulated by HDAC4 in the epigenetic control of satellite cell expansion and fusion.

The pathogenic mechanisms that underlie the progression of remote degeneration after spinal cord injury (SCI) are not fully understood. In this study, we examined the relationship between endoplasmic reticulum (ER) stress and macroautophagy, hereafter autophagy, and its contribution to the secondary damage and outcomes that are associated with remote degeneration after SCI. Using a rat model of spinal cord hemisection at the cervical level, we measured ER stress and autophagy markers in the axotomized neurons of the red nucleus (RN). In SCI animals, mRNA and protein levels of markers of ER stress, such as GRP78, CHOP, and GADD34, increased 1 day after the injury, peaking on Day 5. Notably, in SCI animals, the increase of ER stress markers correlated with a blockade in autophagic flux, as evidenced by the increase in microtubule-associated protein 2 light chain 3 (LC3-II) and p62/SQSTM1 (p62) and the decline in LAMP1 and LAMP2 levels. After injury, treatment with guanabenz protected neurons from UPR failure and increased lysosomes biogenesis, unblocking autophagic flux. These effects correlated with greater activation of TFEB and improved neuronal survival and functional recovery—effects that persisted after suspension of the treatment. Collectively, our results demonstrate that in remote secondary damage, impairments in autophagic flux are intertwined with ER stress, an association that contributes to the apoptotic cell death and functional damage that are observed after SCI.

RUNX2 encodes the master bone transcription factor driving skeletal development in vertebrates, and playing a specific role in craniofacial and skull morphogenesis. The anatomically modern human (AMH) features sequence changes in the RUNX2 locus compared with archaic hominins’ species. We aimed to understand how these changes may have contributed to human skull globularization occurred in recent evolution. We compared in silico AMH and archaic hominins’ genomes, and used mesenchymal stromal cells isolated from skull sutures of craniosynostosis patients for in vitro functional assays. We detected 459 and 470 nucleotide changes in noncoding regions of the AMH RUNX2 locus, compared with the Neandertal and Denisovan genomes, respectively. Three nucleotide changes in the proximal promoter were predicted to alter the binding of the zinc finger protein Znf263 and long-distance interactions with other cis-regulatory regions. By surface plasmon resonance, we selected nucleotide substitutions in the 3’UTRs able to affect miRNA binding affinity. Specifically, miR-3150a-3p and miR-6785-5p expression inversely correlated with RUNX2 expression during in vitro osteogenic differentiation. The expression of two long non-coding RNAs, AL096865.1 and RUNX2-AS1 , within the same locus, was modulated during in vitro osteogenic differentiation and correlated with the expression of specific RUNX2 isoforms. Our data suggest that RUNX2 may have undergone adaptive phenotypic evolution caused by epigenetic and post-transcriptional regulatory mechanisms, which may explain the delayed suture fusion leading to the present-day globular skull shape.

The TerraSAR-X (TSX) mission provides a distinguished collection of high resolution satellite images that shows great promise for a global monitoring of human settlements. Hence, the German Aerospace Center (DLR) has developed the Urban Footprint Processor (UFP) that represents an operational framework for the mapping of built-up areas based on a mass processing and analysis of TSX imagery. The UFP includes functionalities for data management, feature extraction, unsupervised classification, mosaicking, and post-editing. Based on >180.000 TSX StripMap scenes, the UFP was used in 2016 to derive a global map of human presence on Earth in a so far unique spatial resolution of 12 m per grid cell: the Global Urban Footprint (GUF). This work provides a comprehensive summary of the major achievements related to the Global Urban Footprint initiative, with dedicated sections focusing on aspects such as UFP methodology, basic product characteristics (specification, accuracy, global figures on urbanization derived from GUF), the user community, and the already initiated future roadmap of follow-on activities and products. The active community of >250 institutions already working with the GUF data documents the relevance and suitability of the GUF initiative and the underlying high-resolution SAR imagery with respect to the provision of key information on the human presence on earth and the global human settlements properties and patterns, respectively.

Continental to global scale mapping of the human settlement extent based on earth observation satellite data has made considerable progress. Nevertheless, the current approaches only provide a two-dimensional representation of the built environment. Therewith, a full characterization is restricted in terms of the urban morphology and built-up density, which can only be gained by a detailed examination of the vertical settlement extent. This paper introduces a methodology for the extraction of three-dimensional (3D) information on human settlements by analyzing the digital elevation and radar intensity data collected by the German TanDEM-X satellite mission in combination with multispectral Sentinel-2 imagery and data from the Open Street Map initiative and the Global Urban Footprint human settlement mask. The first module of the underlying processor generates a normalized digital surface model from the TanDEM-X digital elevation model for all regions marked as a built-up area by the Global Urban Footprint. The second module generates a building mask based on a joint processing of Open Street Map, TanDEM-X/TerraSAR-X radar images, the calculated normalized digital surface model and Sentinel-2 imagery. Finally, a third module allocates the local relative heights of the normalized digital surface model to the building structures provided by the building mask. The outcome of the procedure is a 3D map of the built environment showing the estimated local height for all identified vertical building structures at 12 m spatial resolution. The results of a first validation campaign based on reference data collected for the seven cities of Amsterdam (NL), Indianapolis (US), Kigali (RW), Munich (DE), New York (US), Vienna (AT), and Washington (US) indicate the potential of the proposed methodology to accurately estimate the distribution of building heights within the built-up area.

Background Embryonal Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma derived from myogenic precursors that is characterized by a good prognosis in patients with localized disease. Conversely, metastatic tumors often relapse, leading to a dismal outcome. The histone methyltransferase EZH2 epigenetically suppresses skeletal muscle differentiation by repressing the transcription of myogenic genes. Moreover, de-regulated EZH2 expression has been extensively implied in human cancers. We have previously shown that EZH2 is aberrantly over-expressed in RMS primary tumors and cell lines. Moreover, it has been recently reported that EZH2 silencing in RD cells, a recurrence-derived embryonal RMS cell line, favors myofiber-like structures formation in a pro-differentiation context. Here we evaluate whether similar effects can be obtained also in the presence of growth factor-supplemented medium (GM), that mimics a pro-proliferative microenvironment, and by pharmacological targeting of EZH2 in RD cells and in RD tumor xenografts. Methods Embryonal RMS RD cells were cultured in GM and silenced for EZH2 or treated with either the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) that induces EZH2 degradation, or with a new class of catalytic EZH2 inhibitors, MC1948 and MC1945, which block the catalytic activity of EZH2. RD cell proliferation and myogenic differentiation were evaluated both in vitro and in vivo . Results Here we show that EZH2 protein was abnormally expressed in 19 out of 19 (100%) embryonal RMS primary tumors and cell lines compared to their normal counterparts. Genetic down-regulation of EZH2 by silencing in GM condition reduced RD cell proliferation up-regulating p21 Cip1 . It also resulted in myogenic-like differentiation testified by the up-regulation of myogenic markers Myogenin , MCK and MHC . These effects were reverted by enforced over-expression of a murine Ezh2, highlighting an EZH2-specific effect. Pharmacological inhibition of EZH2 using either DZNep or MC inhibitors phenocopied the genetic knockdown of EZH2 preventing cell proliferation and restoring myogenic differentiation both in vitro and in vivo . Conclusions These results provide evidence that EZH2 function can be counteracted by pharmacological inhibition in embryonal RMS blocking proliferation even in a pro-proliferative context. They also suggest that this approach could be exploited as a differentiation therapy in adjuvant therapeutic intervention for embryonal RMS.