SummaryBMP signaling plays a crucial role in the establishment of the dorso-ventral body axis in bilaterally symmetric animals. However, the topologies of the bone morphogenetic protein (BMP) signaling networks vary drastically in different animal groups, raising questions about the evolutionary constraints and evolvability of BMP signaling systems. Using loss-of-function analysis and mathematical modeling, we show that two signaling centers expressing different BMPs and BMP antagonists maintain the secondary axis of the sea anemone Nematostella. We demonstrate that BMP signaling is required for asymmetric Hox gene expression and mesentery formation. Computational analysis reveals that network parameters related to BMP4 and Chordin are constrained both in Nematostella and Xenopus, while those describing the BMP signaling modulators can vary significantly. Notably, only chordin, but not bmp4 expression needs to be spatially restricted for robust signaling gradient formation. Our data provide an explanation of the evolvability of BMP signaling systems in axis formation throughout Eumetazoa.

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Mutations in the l(3)mbt tumour suppressor result in overproliferation of Drosophila larval brains. Recently, the derepression of different gene classes in l(3)mbt mutants was shown to be causal for transformation. However, the molecular mechanisms of dL(3)mbt-mediated gene repression are not understood. Here, we identify LINT, the major dL(3)mbt complex of Drosophila. LINT has three core subunits—dL(3)mbt, dCoREST, and dLint-1—and is expressed in cell lines, embryos, and larval brain. Using genome-wide ChIP–Seq analysis, we show that dLint-1 binds close to the TSS of tumour-relevant target genes. Depletion of the LINT core subunits results in derepression of these genes. By contrast, histone deacetylase, histone methylase, and histone demethylase activities are not required to maintain repression. Our results support a direct role of LINT in the repression of brain tumour-relevant target genes by restricting promoter access.

It has been 200 years since Parkinson’s disease (PD) was first described, yet many aspects of its etiopathogenesis remain unclear. PD is a progressive and complex neurodegenerative disorder caused by genetic and environmental factors including aging, nutrition, pesticides and exposure to heavy metals. DNA methylation may be altered in response to some of these factors; therefore, it is proposed that epigenetic mechanisms, particularly DNA methylation, can have a fundamental role in gene–environment interactions that are related with PD. Epigenetic changes in PD-associated genes are now widely studied in different populations, to discover the mechanisms that contribute to disease development and identify novel biomarkers for early diagnosis and future pharmacological treatment. While initial studies sought to find associations between promoter DNA methylation and the regulation of associated genes in PD brain tissue, more recent studies have described concordant DNA methylation patterns between blood and brain tissue DNA. These data justify the use of peripheral blood samples instead of brain tissue for epigenetic studies. Here, we summarize the current data about DNA methylation changes in PD and discuss the potential of DNA methylation as a potential biomarker for PD. Additionally, we discuss environmental and nutritional factors that have been implicated in DNA methylation. Although the search for significant DNA methylation changes and gene expression analyses of PD-associated genes have yielded inconsistent and contradictory results, epigenetic modifications remain under investigation for their potential to reveal the link between environmental risk factors and the development of PD.

Histone modifications play an important role in shaping chromatin structure. Here, we describe the use of an in vitro chromatin assembly system from Drosophila embryo extracts to investigate the dynamic changes of histone modifications subsequent to histone deposition. In accordance with what has been observed in vivo, we find a deacetylation of the initially diacetylated isoform of histone H4, which is dependent on chromatin assembly. Immediately after deposition of the histones onto DNA, H4 is monomethylated at K20, which is required for an efficient deacetylation of the H4 molecule. H4K20 methylation-dependent dl(3)MBT association with chromatin and the identification of a dl(3)MBT-dRPD3 complex suggest that a deacetylase is specifically recruited to the monomethylated substrate through interaction with dl(3)MBT. Our data demonstrate that histone modifications are added and removed during chromatin assembly in a highly regulated manner.All DNA in a eukaryotic cell is assembled into chromatin to fit it into the restricted nuclear space and to organize the genome (29, 56). As the DNA content of a cell doubles during S-phase of the cell cycle, the cell has to provide sufficient histone molecules to package the newly replicated DNA into chromatin. This is achieved mainly by a coupling of histone and DNA synthesis (37). The progression of the DNA replication machinery disrupts the nucleosome in front of the replication fork, which is then reassembled onto the newly synthesized DNA strands in a random manner (15,20). The remaining gaps are subsequently filled up with newly translated histone molecules, leading to a mosaic pattern of new and old histone octamers (2, 21). This process is assisted by the action of nuclear chaperones, which bind to the histones before deposition (14, 34). The newly deposited histones are more loosely associated with the DNA than the bulk histones and mature slowly into a more stable chromatin structure. Assembly is achieved via an ordered deposition of H3 and H4, followed by the binding of H2A/H2B dimers and finally the interaction of the linker histone H1 with the chromatin fiber (19)(20)(21)(22)49).Posttranslational modifications of histone molecules are generally considered to play an important role during the establishment and maintenance of chromatin structures. The combination of histone modifications has been proposed to constitute a "histone code" (23, 55), which is involved in the maintenance of epigenetic information. However, it is unclear how histone modifications are replicated during cellular division and DNA repair when newly translated histones are deposited onto the DNA.Modification marks can be stably maintained through multiple mitotic divisions (3,23,30,55). However, for most histone modifications, the molecular mechanisms that regulate this maintenance have so far remained elusive. A key aspect of this maintenance or reestablishment of modification patterns is the precise copying of histone modification patterns from the parental histone to the newly synthesized on...

BackgroundPost-transcriptional regulation by microRNAs is recognized as one of the major pathways for the control of cellular homeostasis. Less well understood is the transcriptional and epigenetic regulation of genes encoding microRNAs. In the present study we addressed the epigenetic regulation of the miR-181c in normal and malignant brain cells.MethodsTo explore the epigenetic regulation of the miR-181c we evaluated its expression using RT-qPCR and the in vivo binding of the CCCTC-binding factor (CTCF) to its regulatory region in different glioblastoma cell lines. DNA methylation survey, chromatin immunoprecipitation and RNA interference assays were used to assess the role of CTCF in the miR-181c epigenetic silencing.ResultsWe found that miR-181c is downregulated in glioblastoma cell lines, as compared to normal brain tissues. Loss of expression correlated with a notorious gain of DNA methylation at the miR-181c promoter region and the dissociation of the multifunctional nuclear factor CTCF. Taking advantage of the genomic distribution of CTCF in different cell types we propose that CTCF has a local and cell type specific regulatory role over the miR-181c and not an architectural one through chromatin loop formation. This is supported by the depletion of CTCF in glioblastoma cells affecting the expression levels of NOTCH2 as a target of miR-181c.ConclusionTogether, our results point to the epigenetic role of CTCF in the regulation of microRNAs implicated in tumorigenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2273-6) contains supplementary material, which is available to authorized users.

In mammals, DNA methylation is a crucial epigenetic modification with key functions during development. Cellular processes that are regulated by DNA methylation comprise X chromosome inactivation, gene imprinting, genomic stability and transcriptional regulation. Generally, the methylation status of the majority of target sites is reliably propagated during mitosis. However, advances in genome-wide DNA methylation analysis at base-resolution have discovered a substantial amount of differential DNA methylation between normal cells of different tissue-origin. Moreover, aberrant DNA methylation changes are linked with a significant number of human diseases, particularly with cancer. Sites of differential and aberrant DNA methylation include regulatory DNA sequences, such as CpG islands in promoters and distal -regulatory elements, like enhancers. In this review, we will discuss novel aspects of DNA methylation dynamics, during normal development and in association with diseases.

Zoonotic species of the Chlamydiaceae family should be considered as rare pathogenic agents of severe atypical pneumonia. A fatal case of a severe pneumonia due to Chlamydia psittaci was traced back to pet birds, and pneumonia in a pregnant woman was attributed to abortions in a sheep and goat flock, being the source of Chlamydia abortus. The two SARS‑CoV‑2-negative pneumonia cases presented here were investigated in an inter-disciplinary approach involving physicians and veterinarians. State-of-art molecular methods allowed the identification and genotyping of zoonotic Chlamydiae.