De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD

Epidemiology and clinical features of gastroenteritis in hospitalised children: prospective survey during a 2-year period in a Parisian hospital, France

International audienceRotavirus is recognised as the most important agent of severe acute gastroenteritis (AGE) in young children. In a 2-year prospective survey, we investigated the epidemiology and clinical features of the viral and bacterial pathogens in children hospitalised for AGE. The study was performed in a Parisian teaching hospital from November 2001 to May 2004. Clinical data were prospectively collected to assess the gastroenteritis severity (20-point Vesikari severity score, the need for intravenous rehydration, duration of hospitalisation). Stools were systematically tested for group A rotavirus, norovirus, astrovirus and adenovirus 40/41, sapovirus and Aichi virus and enteropathogenic bacteria. A total of 457 children (mean age 15.9 months) were enrolled. Viruses were detected in 305 cases (66.7%) and bacteria in 31 cases (6.8%). Rotaviruses were the most frequent pathogen (48.8%), followed by noroviruses (8.3%) and adenoviruses, astroviruses, Aichi viruses and sapoviruses in 3.5%, 1.5%, 0.9% and 0.4%, respectively. Cases of rotavirus gastroenteritis were significantly more severe than those of norovirus with respect to the Vesikari score, duration of hospitalisation and the need for intravenous rehydration. Rotaviruses were the most frequent and most severe cause in children hospitalised for AGE, and noroviruses also account for a large number of cases in this population

The influence of DNA methylation on monoallelic expression

© 2019 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND).Monoallelic gene expression occurs in diploid cells when only one of the two alleles of a gene is active. There are three main classes of genes that display monoallelic expression in mammalian genomes: (1) imprinted genes that are monoallelically expressed in a parent-of-origin dependent manner; (2) X-linked genes that undergo random X-chromosome inactivation in female cells; (3) random monoallelically expressed single and clustered genes located on autosomes. The heritability of monoallelic expression patterns during cell divisions implies that epigenetic mechanisms are involved in the cellular memory of these expression states. Among these, methylation of CpG sites on DNA is one of the best described modification to explain somatic inheritance. Here, we discuss the relevance of DNA methylation for the establishment and maintenance of monoallelic expression patterns among these three groups of genes, and how this is intrinsically linked to development and cellular states.This work was supported by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES), Portugal, through the project grants PTDC/BEX-BCM/2612/2014 and PTDC/BIA-MOL/29320/2017 IC&DT. S.T.d.R. has a CEECUIND/01234/207 assistant research contract from FCT. A.-V.G. is supported by an INSERM investigator position. Publications costs were supported by UID/BIM/50005/2019, project funded by FCT/MCTES through Fundos do Orçamento de Estado.info:eu-repo/semantics/publishedVersio

A cellular and regulatory map of the GABAergic nervous system of C. elegans

Neurotransmitter maps are important complements to anatomical maps and represent an invaluable resource to understand nervous system function and development. We report here a comprehensive map of neurons in the C. elegans nervous system that contain the neurotransmitter GABA, revealing twice as many GABA-positive neuron classes as previously reported. We define previously unknown glia-like cells that take up GABA, as well as 'GABA uptake neurons' which do not synthesize GABA but take it up from the extracellular environment, and we map the expression of previously uncharacterized ionotropic GABA receptors. We use the map of GABA-positive neurons for a comprehensive analysis of transcriptional regulators that define the GABA phenotype. We synthesize our findings of specification of GABAergic neurons with previous reports on the specification of glutamatergic and cholinergic neurons into a nervous system-wide regulatory map which defines neurotransmitter specification mechanisms for more than half of all neuron classes in C. elegans

Sens et plaisirs de la forme narrative

Il y a un sens premier du récit (celui de l’histoire racontée), voire un sens second (la thèse exemplifiée par ladite histoire) ; mais l’important est souvent ailleurs : dans la forme sensible du texte, qui conduit le lecteur à un plaisir sensuel, affectif, ou même intellectuel. Les très grandes œuvres parviennent sans doute – et c’est l’une des raisons de leur gloire et de leur survie – à jouer non seulement sur le plaisir sensible de la forme et sur sa dimension affective, mais aussi sur la stimulation de l’intellect : les formes prennent alors un poids existentiel, concurrençant le contenu même de ce qui est dit.There is a primary meaning of the narrative (that of the story told), even a secondary meaning (the thesis exemplified by said story); but the important thing is often elsewhere: in the sensitive form of the text, which leads the reader to a sensual, affective, or even intellectual pleasure. The very great works no doubt manage – and this is one of the reasons for their fame and their survival – to play not only on the perceptible pleasure of the form and on its affective dimension, but also on the stimulation of the intellect: the forms then take an existential weight, competing with the very content of what is said

Mutually exclusive sense–antisense transcription at FLC facilitates environmentally induced gene repression

Antisense transcription through genic regions is pervasive in most genomes; however, its functional significance is still unclear. We are studying the role of antisense transcripts (COOLAIR) in the cold-induced, epigenetic silencing of Arabidopsis FLOWERING LOCUS C (FLC), a regulator of the transition to reproduction. Here we use single-molecule RNA FISH to address the mechanistic relationship of FLC and COOLAIR transcription at the cellular level. We demonstrate that while sense and antisense transcripts can co-occur in the same cell they are mutually exclusive at individual loci. Cold strongly upregulates COOLAIR transcription in an increased number of cells and through the mutually exclusive relationship facilitates shutdown of sense FLC transcription in cis. COOLAIR transcripts form dense clouds at each locus, acting to influence FLC transcription through changed H3K36me3 dynamics. These results may have general implications for other loci showing both sense and antisense transcription

X-Chromosome Inactivation and Autosomal Random Monoallelic Expression as “Faux Amis”

Funding: The work of NK and VMB was funded by iNOVA4Health – UIDB/Multi/04462/2020 and UIDP/Multi/04462/2020, a program financially supported by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Educação e Ciência through national funds, and the FCT grant PTDC/BEX-BCM/5900/2014. CFA-P has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 752806. A-VG was supported by Fundação para a Ciência e Tecnologia (FCT), Portugal, through an assistant research contract (CEECIND/02085/2018) and the project grant PTDC/MEDOUT/4301/2020 IC&DT.X-chromosome inactivation (XCI) and random monoallelic expression of autosomal genes (RMAE) are two paradigms of gene expression regulation where, at the single cell level, genes can be expressed from either the maternal or paternal alleles. X-chromosome inactivation takes place in female marsupial and placental mammals, while RMAE has been described in mammals and also other species. Although the outcome of both processes results in random monoallelic expression and mosaicism at the cellular level, there are many important differences. We provide here a brief sketch of the history behind the discovery of XCI and RMAE. Moreover, we review some of the distinctive features of these two phenomena, with respect to when in development they are established, their roles in dosage compensation and cellular phenotypic diversity, and the molecular mechanisms underlying their initiation and stability.publishersversionpublishe

Genomic insights into cancer-associated aberrant CpG island hypermethylation

Carcinogenesis is thought to occur through a combination of mutational and epimutational events that disrupt key pathways regulating cellular growth and division. The DNA methylomes of cancer cells can exhibit two striking differences from normal cells; a global reduction of DNA methylation levels and the aberrant hypermethylation of some sequences, particularly CpG islands (CGIs). This aberrant hypermethylation is often invoked as a mechanism causing the transcriptional inactivation of tumour suppressor genes that directly drives the carcinogenic process. Here, we review our current understanding of this phenomenon, focusing on how global analysis of cancer methylomes indicates that most affected CGI genes are already silenced prior to aberrant hypermethylation during cancer development. We also discuss how genome-scale analyses of both normal and cancer cells have refined our understanding of the elusive mechanism(s) that may underpin aberrant CGI hypermethylation

Circadian control of abscisic acid biosynthesis and signalling pathways revealed by genome-wide analysis of LHY binding targets

The LATE ELONGATED HYPOCOTYL (LHY) transcription factor functions as part of the oscillatory mechanism of the Arabidopsis circadian clock. This paper reports the genome‐wide analysis of its binding targets and reveals a role in the control of abscisic acid (ABA) biosynthesis and downstream responses. LHY directly repressed expression of 9‐cis‐epoxycarotenoid dioxygenase enzymes, which catalyse the rate‐limiting step of ABA biosynthesis. This suggested a mechanism for the circadian control of ABA accumulation in wild‐type plants. Consistent with this hypothesis, ABA accumulated rhythmically in wild‐type plants, peaking in the evening. LHY‐overexpressing plants had reduced levels of ABA under drought stress, whereas loss‐of‐function mutants exhibited an altered rhythm of ABA accumulation. LHY also bound the promoter of multiple components of ABA signalling pathways, suggesting that it may also act to regulate responses downstream of the hormone. LHY promoted expression of ABA‐responsive genes responsible for increased tolerance to drought and osmotic stress but alleviated the inhibitory effect of ABA on seed germination and plant growth. This study reveals a complex interaction between the circadian clock and ABA pathways, which is likely to make an important contribution to plant performance under drought and osmotic stress conditions

NTAP: for NimbleGen tiling array ChIP-chip data analysis

Summary:NTAP is designed to analyze ChIP-chip data generated by the NimbleGen tiling array platform and to accomplish various pattern recognition tasks that are useful especially for epigenetic studies. The modular design of NTAP makes the data processing highly customizable. Users can either use NTAP to perform the full process of NimbleGen tiling array data analysis, or choose post-processing modules in NTAP to analyze pre-processed epigenetic data generated by other platforms. The output of NTAP can be saved in standard GFF format files and visualized in GBrowse