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Pervasive enhancer transcription is at the origin of more than half of all long noncoding RNAs in humans. Transcription of enhancer-associated long noncoding RNAs (elncRNA) contribute to their cognate enhancer activity and gene expression regulation in cis . Recently, splicing of elncRNAs was shown to be associated with elevated enhancer activity. However, whether splicing of elncRNA transcripts is a mere consequence of accessibility at highly active enhancers or if elncRNA splicing directly impacts enhancer function, remains unanswered. We analysed genetically driven changes in elncRNA splicing, in humans, to address this outstanding question. We showed that splicing related motifs within multi-exonic elncRNAs evolved under selective constraints during human evolution, suggesting the processing of these transcripts is unlikely to have resulted from transcription across spurious splice sites. Using a genome-wide and unbiased approach, we used nucleotide variants as independent genetic factors to directly assess the causal relationship that underpin elncRNA splicing and their cognate enhancer activity. We found that the splicing of most elncRNAs is associated with changes in chromatin signatures at cognate enhancers and target mRNA expression. We provide evidence that efficient and conserved processing of enhancer-associated elncRNAs contributes to enhancer activity.

The authors present a case of acute disseminated encephalomyelitis in a COVID-19 pediatric patient with positive SARS-CoV2 markers from a nasopharyngeal swab. A previously healthy 12-year-old-girl presented with a skin rash, headache, and fever. Five days after that, she had an acute, progressive, bilateral, and symmetrical motor weakness. She evolved to respiratory failure. Magnetic resonance imaging (MRI) of the brain and cervical spine showed extensive bilateral and symmetric restricted diffusion involving the subcortical and deep white matter, a focal hyperintense T2/FLAIR lesion in the splenium of the corpus callosum with restricted diffusion, and extensive cervical myelopathy involving both white and gray matter. Follow-up examinations of the brain and spine were performed 30 days after the first MRI examination. The images of the brain demonstrated mild dilatation of the lateral ventricles and widespread widening of the cerebral sulci, complete resolution of the extensive white matter restricted diffusion, and complete resolution of the restricted diffusion in the lesion of the splenium of the corpus callosum, leaving behind a small gliotic focus. The follow-up examination of the spine demonstrated nearly complete resolution of the extensive signal changes in the spinal cord, leaving behind scattered signal changes in keeping with gliosis. She evolved with partial clinical and neurological improvement and was subsequently discharged.

Mammalian sex chromosomes stem from ancestral autosomes and have substantially differentiated. It was shown that X-linked genes have generated duplicate intronless gene copies (retrogenes) on autosomes due to this differentiation. However, the precise driving forces for this out-of-X gene \"movement\" and its evolutionary onset are not known. Based on expression analyses of male germ-cell populations, we here substantiate and extend the hypothesis that autosomal retrogenes functionally compensate for the silencing of their X-linked housekeeping parental genes during, but also after, male meiotic sex chromosome inactivation (MSCI). Thus, sexually antagonistic forces have not played a major role for the selective fixation of X-derived gene copies in mammals. Our dating analyses reveal that although retrogenes were produced ever since the common mammalian ancestor, selectively driven retrogene export from the X only started later, on the placental mammal (eutherian) and marsupial (metatherian) lineages, respectively. Together, these observations suggest that chromosome-wide MSCI emerged close to the eutherian-marsupial split approximately 180 million years ago. Given that MSCI probably reflects the spread of the recombination barrier between the X and Y, crucial for their differentiation, our data imply that these chromosomes became more widely differentiated only late in the therian ancestor, well after the divergence of the monotreme lineage. Thus, our study also provides strong independent support for the recent notion that our sex chromosomes emerged, not in the common ancestor of all mammals, but rather in the therian ancestor, and therefore are much younger than previously thought.

The origin of new genes through gene duplication is fundamental to the evolution of lineage- or species-specific phenotypic traits. In this report, we estimate the number of functional retrogenes on the lineage leading to humans generated by the high rate of retroposition (retroduplication) in primates. Extensive comparative sequencing and expression studies coupled with evolutionary analyses and simulations suggest that a significant proportion of recent retrocopies represent bona fide human genes. We estimate that at least one new retrogene per million years emerged on the human lineage during the past approximately 63 million years of primate evolution. Detailed analysis of a subset of the data shows that the majority of retrogenes are specifically expressed in testis, whereas their parental genes show broad expression patterns. Consistently, most retrogenes evolved functional roles in spermatogenesis. Proteins encoded by X chromosome-derived retrogenes were strongly preserved by purifying selection following the duplication event, supporting the view that they may act as functional autosomal substitutes during X-inactivation of late spermatogenesis genes. Also, some retrogenes acquired a new or more adapted function driven by positive selection. We conclude that retroduplication significantly contributed to the formation of recent human genes and that most new retrogenes were progressively recruited during primate evolution by natural and/or sexual selection to enhance male germline function.

The relative ease of mouse Embryonic Stem Cells (mESCs) culture and the potential of these cells to differentiate into any of the three primary germ layers: ectoderm, endoderm and mesoderm (pluripotency), makes them an ideal and frequently used system to dissect how gene expression changes impact cell state and differentiation. These efforts are further supported by the large number of constitutive and inducible mESC mutants established with the aim of assessing the contributions of different pathways and genes to cell homeostasis and gene regulation. Gene product abundance is controlled by the modulation of the rates of RNA synthesis, processing, and degradation. The ability to determine the relative contribution of these different RNA metabolic rates to gene expression control using standard RNA-sequencing approaches, which only capture steady state abundance of transcripts, is limited. In contrast, metabolic labeling of RNA with 4-thiouridine (4sU) coupled with RNA-sequencing, allows simultaneous and reproducible inference of transcriptome wide synthesis, processing, and degradation rates. Here we describe, a detailed protocol for 4sU metabolic labeling in mESCs that requires short 4sU labeling times at low concentration and minimally impacts cellular homeostasis. This approach presents a versatile method for in-depth characterization of the gene regulatory strategies governing gene steady state abundance in mESC.

The mechanisms underlying the neurodevelopmental deficits associated with CHARGE syndrome, which include cerebellar hypoplasia, developmental delay, coordination problems, and autistic features, have not been identified. CHARGE syndrome has been associated with mutations in the gene encoding the ATP-dependent chromatin remodeler CHD7. CHD7 is expressed in neural stem and progenitor cells, but its role in neurogenesis during brain development remains unknown. Here we have shown that deletion of Chd7 from cerebellar granule cell progenitors (GCps) results in reduced GCp proliferation, cerebellar hypoplasia, developmental delay, and motor deficits in mice. Genome-wide expression profiling revealed downregulated expression of the gene encoding the glycoprotein reelin (Reln) in Chd7-deficient GCps. Recessive RELN mutations have been associated with severe cerebellar hypoplasia in humans. We found molecular and genetic evidence that reductions in Reln expression contribute to GCp proliferative defects and cerebellar hypoplasia in GCp-specific Chd7 mouse mutants. Finally, we showed that CHD7 is necessary for maintaining an open, accessible chromatin state at the Reln locus. Taken together, this study shows that Reln gene expression is regulated by chromatin remodeling, identifies CHD7 as a previously unrecognized upstream regulator of Reln, and provides direct in vivo evidence that a mammalian CHD protein can control brain development by modulating chromatin accessibility in neuronal progenitors.

To generate energy efficiently, the cell is uniquely challenged to co-ordinate the abundance of electron transport chain protein subunits expressed from both nuclear and mitochondrial genomes. How an effective stoichiometry of this many constituent subunits is co-ordinated post-transcriptionally remains poorly understood. Here we show that Cerox1 , an unusually abundant cytoplasmic long noncoding RNA (lncRNA), modulates the levels of mitochondrial complex I subunit transcripts in a manner that requires binding to microRNA-488-3p. Increased abundance of Cerox1 cooperatively elevates complex I subunit protein abundance and enzymatic activity, decreases reactive oxygen species production, and protects against the complex I inhibitor rotenone. Cerox1 function is conserved across placental mammals: human and mouse orthologues effectively modulate complex I enzymatic activity in mouse and human cells, respectively. Cerox1 is the first lncRNA demonstrated, to our knowledge, to regulate mitochondrial oxidative phosphorylation and, with miR-488-3p, represent novel targets for the modulation of complex I activity. Animal cells generate over 90% of the energy they need within small structures called mitochondria. Converting food into energy requires many different proteins and cells control the relative amounts of the proteins in mitochondria to ensure this process is efficient. To make more of a given protein, the cell must copy the DNA of the gene that encodes it into another molecule known as a messenger RNA, before reading the instructions in the messenger RNA to build the protein. However, this is not the only way that a cell uses molecules of RNA. A second group of RNAs called long non-coding RNAs (or lncRNAs) can help regulate the production of proteins in complex ways, and each lncRNA can have an effect across multiple genes. Some lncRNAs, for example, stop a third group of RNAs – microRNAs – from blocking certain messenger RNAs from being read. Sirey et al. set out to answer whether a lncRNA might help to co-ordinate the production of the many proteins needed by mitochondria. In experiments with mouse cells grown in the laboratory, Sirey et al. identified a lncRNA called Cerox1 that can co-ordinate the levels of at least 12 mitochondrial proteins. A microRNA called miR-488-3p suppresses the production of many of these proteins. By binding to miR-488-3p, Cerox1 blocks the effects of the microRNA so more proteins are produced. Sirey et al. artificially altered the amount of Cerox1 in the cells and showed that more Cerox1 leads to higher mitochondria activity. Further experiments revealed that this same control system also exists in human cells. Mitochondria are vital to cell survival and changes that affect their efficiency can be fatal or highly debilitating. Reduced efficiency is also a hallmark of ageing and contributes to conditions including cardiovascular disease, diabetes and Parkinson’s disease. Understanding how mitochondria are regulated could unlock new treatment methods for these conditions, while a better understanding of the co-ordination of protein production offers other insights into some of the most fundamental biology.

Esta apresentação consiste em um mapeamento, não exaustivo, das contribuições dos textos escritos a várias mãos pelas colaboradoras deste dossiê, também inspirado nos debates ocorridos por ocasião do 4°Seminário Casa, Corpo e Políticas da Terra. A perspectiva de gênero adotada nas abordagens etnográficas em domínios subdisciplinares distintos promove deslocamentos teóricos e analíticos, assim como nas dicotomias centrais da antropologia. This presentation consists of a non-exhaustive mapping of the contributions of the texts written by various hands by the contributors to this dossier, also inspired by the debates that took place at the 4th Seminar on House, body and politics of the land. The gender perspective adopted in ethnographic approaches in different subdisciplinary domains promotes theoretical and analytical shifts, as well as in the central dichotomies of anthropology

Gene duplication was prevalent during hominoid evolution, yet little is known about the functional fate of new ape gene copies. We characterized the CDC14B cell cycle gene and the functional evolution of its hominoid-specific daughter gene, CDC14Bretro. We found that CDC14B encodes four different splice isoforms that show different subcellular localizations (nucleus or microtubule-associated) and functional properties. A microtubular CDC14B variant spawned CDC14Bretro through retroposition in the hominoid ancestor 18-25 million years ago (Mya). CDC14Bretro evolved brain-/testis-specific expression after the duplication event and experienced a short period of intense positive selection in the African ape ancestor 7-12 Mya. Using resurrected ancestral protein variants, we demonstrate that by virtue of amino acid substitutions in distinct protein regions during this time, the subcellular localization of CDC14Bretro progressively shifted from the association with microtubules (stabilizing them) to an association with the endoplasmic reticulum. CDC14Bretro evolution represents a paradigm example of rapid, selectively driven subcellular relocalization, thus revealing a novel mode for the emergence of new gene function.