Mapping the developmental trajectory of human astrocytes reveals divergence in glioblastoma.

Glioblastoma (GBM) is defined by heterogeneous and resilient cell populations that closely reflect neurodevelopmental cell types. Although it is clear that GBM echoes early and immature cell states, identifying the specific developmental programmes disrupted in these tumours has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM.

Ectopic transcription due to inappropriately inherited histone methylation may interfere with the ongoing function of terminally differentiated cells.

How mutations in histone modifying enzymes lead to neurodevelopmental disorders is unknown. We took advantage of the invariant embryonic lineage and adult nervous system in C. elegans to investigate a double mutant between spr-5/Lsd1/Kdm1a (H3K4me1/2 demethylase) and met-2/Setdb1 (H3K9 methyltransferase).

Characterization of a strain-specific CD-1 reference genome reveals potential inter- and intra-strain functional variability.

Background: CD-1 is an outbred mouse stock that is frequently used in toxicology, pharmacology, and fundamental biomedical research. Although inbred strains are typically better suited for such studies due to minimal genetic variability, outbred stocks confer practical advantages over inbred strains, such as improved breeding performance and low cost. Knowledge of the full genetic variability of CD-1 would make it more useful in toxicology, pharmacology, and fundamental biomedical research.

pTDP-43 levels correlate with cell type specific molecular alterations in the prefrontal cortex of ALS/FTD patients.

Repeat expansions in the gene are the most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place in the dorsolateral frontal cortex of patients with ALS/FTD, we compared healthy controls with ALS/FTD donor samples staged based on the levels of cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark of disease progression. We identified distinct molecular changes in different cell types that take place during FTD development.

Recruitment of CTCF to an enhancer is responsible for transgenerational inheritance of BPA-induced obesity.

The mechanisms by which environmentally-induced epiphenotypes are transmitted transgenerationally in mammals are poorly understood. Here we show that exposure of pregnant mouse females to bisphenol A (BPA) results in obesity in the F2 progeny due to increased food intake. This epiphenotype can be transmitted up to the F6 generation.

Expansion of the genotypic and phenotypic spectrum of CTCF-related disorder guides clinical management: 43 new subjects and a comprehensive literature review.

Monoallelic variants of CTCF cause an autosomal dominant neurodevelopmental disorder with a wide range of features, including impacts on the brain, growth, and craniofacial development. A growing number of subjects with CTCF-related disorder (CRD) have been identified due to the increased application of exome sequencing, and further delineation of the clinical spectrum of CRD is needed. Here, we examined the clinical features, including facial profiles, and genotypic spectrum of 107 subjects with identified CTCF variants, including 43 new and 64 previously described subjects.

The Cupid shuffle: Do enhancers prefer specific promoters?

Two recent reports (Martinez-Ara et al., 2022; Bergman et al., 2022) explore the compatibility between enhancers and promoters and find that enhancers preferentially activate promoters with low intrinsic activity rather than favoring housekeeping or cell-type-specific promoters.

Beyond Genes: Germline Disruption in the Etiology of Autism Spectrum Disorders.

Investigations into the etiology of autism spectrum disorders have been largely confined to two realms: variations in DNA sequence and somatic developmental exposures. Here we suggest a third route-disruption of the germline epigenome induced by exogenous toxicants during a parent's gamete development. Similar to cases of germline mutation, these molecular perturbations may produce dysregulated transcription of brain-related genes during fetal and early development, resulting in abnormal neurobehavioral phenotypes in offspring.

Is developmental synchrony enabled by CTCF residence time?

Depletion of CTCF in cultured cells has minor effects on transcription whereas its mutation leads to embryonic lethality and developmental defects. In a recent issue of Nature Cell Biology, Soochit et al. (2021) show that the residence time of CTCF on DNA may explain its critical role in cell differentiation.

Exposure to sevoflurane results in changes of transcription factor occupancy in sperm and inheritance of autism†.

One in 54 children in the United States is diagnosed with autism spectrum disorder. De novo germline and somatic mutations cannot account for all cases of autism spectrum disorder, suggesting that epigenetic alterations triggered by environmental exposures may be responsible for a subset of autism spectrum disorder cases. Human and animal studies have shown that exposure of the developing brain to general anesthetic agents can trigger neurodegeneration and neurobehavioral abnormalities, but the effects of general anesthetics on the germline have not been explored in detail.

Novel mRNAs 3' end-associated -regulatory elements with epigenomic signatures of mammalian enhancers in the genome.

The precise spatial and temporal control of gene expression requires the coordinated action of genomic -regulatory elements (CREs), including transcriptional enhancers. However, our knowledge of enhancers in plants remains rudimentary and only a few plant enhancers have been experimentally defined. Here, we screened the genome and identified >1900 unique candidate CREs that carry the genomic signatures of mammalian enhancers.

An Overview of Methodologies in Studying lncRNAs in the High-Throughput Era: When Acronyms ATTACK!

The discovery of pervasive transcription in eukaryotic genomes provided one of many surprising (and perhaps most surprising) findings of the genomic era and led to the uncovering of a large number of previously unstudied transcriptional events. This pervasive transcription leads to the production of large numbers of noncoding RNAs (ncRNAs) and thus opened the window to study these diverse, abundant transcripts of unclear relevance and unknown function. Since that discovery, recent advances in high-throughput sequencing technologies have identified a large collection of ncRNAs, from microRNAs to long noncoding RNAs (lncRNAs).

Long Noncoding RNAs in Plants.

The eukaryotic genomes are pervasively transcribed. In addition to protein-coding RNAs, thousands of long noncoding RNAs (lncRNAs) modulate key molecular and biological processes. Most lncRNAs are found in the nucleus and associate with chromatin, but lncRNAs can function in both nuclear and cytoplasmic compartments.

Small RNAs: essential regulators of gene expression and defenses against environmental stresses in plants.

Eukaryotic genomes produce thousands of diverse small RNAs (smRNAs), which play vital roles in regulating gene expression in all conditions, including in survival of biotic and abiotic environmental stresses. SmRNA pathways intersect with most of the pathways regulating different steps in the life of a messenger RNA (mRNA), starting from transcription and ending at mRNA decay. SmRNAs function in both nuclear and cytoplasmic compartments; the regulation of mRNA stability and translation in the cytoplasm and the epigenetic regulation of gene expression in the nucleus are the main and best-known modes of smRNA action.

Stress-induced endogenous siRNAs targeting regulatory intron sequences in Brachypodium.

Exposure to abiotic stresses triggers global changes in the expression of thousands of eukaryotic genes at the transcriptional and post-transcriptional levels. Small RNA (smRNA) pathways and splicing both function as crucial mechanisms regulating stress-responsive gene expression. However, examples of smRNAs regulating gene expression remain largely limited to effects on mRNA stability, translation, and epigenetic regulation.

The role of the Arabidopsis Exosome in siRNA-independent silencing of heterochromatic loci.

The exosome functions throughout eukaryotic RNA metabolism and has a prominent role in gene silencing in yeast. In Arabidopsis, exosome regulates expression of a "hidden" transcriptome layer from centromeric, pericentromeric, and other heterochromatic loci that are also controlled by small (sm)RNA-based de novo DNA methylation (RdDM). However, the relationship between exosome and smRNAs in gene silencing in Arabidopsis remains unexplored.

GAL1-SceI directed site-specific genomic (gsSSG) mutagenesis: a method for precisely targeting point mutations in S. cerevisiae.

Background: Precise targeted mutations are defined as targeted mutations that do not require the retention of other genetic changes, such as marker genes, near the mutation site. In the yeast, S. cerevisiae, there are several methods for introducing precise targeted mutations, all of which depend on inserting both a counter-selectable marker and DNA bearing the mutation.