Mecp2 is an X-linked gene encoding a nuclear protein that binds specifically to methylated DNA (ref. 1) and functions as a general transcriptional repressor by associating with chromatin-remodeling complexes. Mecp2 is expressed at high levels in the postnatal brain, indicating that methylation-dependent regulation of gene expression may have a crucial role in the mammalian central nervous system. Consistent with this notion is the recent demonstration that MECP2 mutations cause Rett syndrome (RTT, MIM 312750), a childhood neurological disorder that represents one of the most common causes of mental retardation in females. Here we show that Mecp2-deficient mice exhibit phenotypes that resemble some of the symptoms of RTT patients. Mecp2-null mice were normal until 5 weeks of age, when they began to develop disease, leading to death between 6 and 12 weeks. Mutant brains showed substantial reduction in both weight and neuronal cell size, but no obvious structural defects or signs of neurodegeneration. Brain-specific deletion of Mecp2 at embryonic day (E) 12 resulted in a phenotype identical to that of the null mutation, indicating that the phenotype is caused by Mecp2 deficiency in the CNS rather than in peripheral tissues. Deletion of Mecp2 in postnatal CNS neurons led to a similar neuronal phenotype, although at a later age. Our results indicate that the role of Mecp2 is not restricted to the immature brain, but becomes critical in mature neurons. Mecp2 deficiency in these neurons is sufficient to cause neuronal dysfunction with symptomatic manifestation similar to Rett syndrome.

Genome-wide demethylation has been suggested to be a step in carcinogenesis. Evidence for this notion comes from the frequently observed global DNA hypomethylation in tumour cells, and from a recent study suggesting that defects in DNA methylation might contribute to the genomic instability of some colorectal tumour cell lines. DNA hypomethylation has also been associated with abnormal chromosomal structures, as observed in cells from patients with ICF (Immunodeficiency, Centromeric instability and Facial abnormalities) syndrome and in cells treated with the demethylating agent 5-azadeoxycytidine. Here we report that murine embryonic stem cells nullizygous for the major DNA methyltransferase (Dnmt1) gene exhibited significantly elevated mutation rates at both the endogenous hypoxanthine phosphoribosyltransferase (Hprt) gene and an integrated viral thymidine kinase (tk) transgene. Gene deletions were the predominant mutations at both loci. The major cause of the observed tk deletions was either mitotic recombination or chromosomal loss accompanied by duplication of the remaining chromosome. Our results imply an important role for mammalian DNA methylation in maintaining genome stability.

DNA methyltransferase I (Dnmt1), the maintenance enzyme for DNA cytosine methylation, is expressed at high levels in the CNS during embryogenesis and after birth. Because embryos deficient for Dnmt1 die at gastrulation, the role of Dnmt1 in the development and function of the nervous system could not be studied by using this mutation. We therefore used the cre/loxP system to produce conditional mutants that lack Dnmt1 in neuroblasts of embryonic day 12 embryos or in postmitotic neurons of the postnatal animal. Conditional deletion of the Dnmt1 gene resulted in rapid depletion of Dnmt1 proteins, indicating that the enzyme in postmitotic neurons turns over quickly. Dnmt1 deficiency in postmitotic neurons neither affected levels of global DNA methylation nor influenced cell survival during postnatal life. In contrast, Dnmt1 deficiency in mitotic CNS precursor cells resulted in DNA hypomethylation in daughter cells. Whereas mutant embryos carrying 95% hypomethylated cells in the brain died immediately after birth because of respiratory distress, mosaic animals with 30% hypomethylated CNS cells were viable into adulthood. However, these mutant cells were eliminated quickly from the brain within 3 weeks of postnatal life. Thus, hypomethylated CNS neurons were impaired functionally and were selected against at postnatal stages.

The Mecp2 gene has been shown to be mutated in most cases of human Rett syndrome, and mouse models deleted for the ortholog have been generated. Lineage-specific deletion of the gene indicated that the Rett-like phenotype is caused by Mecp2 deficiency in neurons. Biochemical evidence suggests that Mecp2 acts as a global transcriptional repressor, predicting that mutant mice should have genome-wide transcriptional deregulation. We tested this hypothesis by comparing global gene expression in wild-type and Mecp2 mutant mice. The results of numerous microarray analyses revealed no dramatic changes in transcription even in mice displaying overt disease symptoms, although statistical power analyses of the data indicated that even a small number of relatively subtle changes in transcription would have been detected if present. However, a classifier consisting of a combined small set of genes was able to distinguish between mutant and wild-type samples with high accuracy. This result suggests that Mecp2 deficiency leads to subtle gene expression changes in mutant brains which may be associated with the phenotypic changes observed.

No abstract

We aim to provide a systematic review and meta-analysis of the prevalence rates of mental health symptoms among major African populations during the COVID-19 pandemic. We include articles from PubMed, Embase, Web of Science, PsycINFO, and medRxiv between 1 February 2020 and 6 February 2021, and pooled data using random-effects meta-analyses. We identify 28 studies and 32 independent samples from 12 African countries with a total of 15,071 participants. The pooled prevalence of anxiety was 37% in 27 studies, of depression was 45% in 24 studies, and of insomnia was 28% in 9 studies. The pooled prevalence rates of anxiety, depression, and insomnia in North Africa (44%, 55%, and 31%, respectively) are higher than those in Sub-Saharan Africa (31%, 30%, and 24%, respectively). We find (a) a scarcity of studies in several African countries with a high number of COVID-19 cases; (b) high heterogeneity among the studies; (c) the extent and pattern of prevalence of mental health symptoms in Africa is high and differs from elsewhere—more African adults suffer from depression rather than anxiety and insomnia during COVID 19 compared to adult populations in other countries/regions. Hence, our findings carry crucial implications and impact future research to enable evidence-based medicine in Africa.

No abstract

Although Huntington’s disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (p < 10−7) associated with 33 CpG sites, including the HTT gene (p = 6.5 × 10−26). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model (p = 6.0 × 10−8) and in the transgenic sheep model (p = 2.4 × 10−88). We define a measure of HD motor score progression among manifest HD cases based on multiple clinical assessments. EWAS of motor progression in manifest HD cases exhibits significant (p < 10−7) associations with methylation levels at three loci: near PEX14 (p = 9.3 × 10−9), GRIK4 (p = 3.0 × 10−8), and COX4I2 (p = 6.5 × 10−8). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.