RNA polymerase II pausing in development: orchestrating transcription

The coordinated regulation of transcriptional networks underpins cellular identity and developmental progression. RNA polymerase II promoter-proximal pausing (Pol II pausing) is a prevalent mechanism by which cells can control and synchronize transcription. Pol II pausing regulates the productive elongation step of transcription at key genes downstream of a variety of signalling pathways, such as FGF and Nodal. Recent advances in our understanding of the Pol II pausing machinery and its role in transcription call for an assessment of these findings within the context of development. In this review, we discuss our current understanding of the molecular basis of Pol II pausing and its function during organismal development. By critically assessing the tools used to study this process we conclude that combining recently developed genomics approaches with refined perturbation systems has the potential to expand our understanding of Pol II pausing mechanistically and functionally in the context of development and beyond.

Acquisition of the counting principles during the subset-knower stages: Insights from children’s errors

Studies on children’s understanding of counting examine when and how children acquire the cardinal principle: the idea that the last word in a counted set reflects the cardinal value of the set. Using Wynn’s (1990) Give-N Task, researchers classify children who can count to generate large sets as having acquired the cardinal principle (cardinal-principle-knowers) and those who cannot as lacking knowledge of it (subset-knowers). However, recent studies have provided a more nuanced view of number word acquisition. Here, we explore this view by examining the developmental progression of the counting principles with an aim to elucidate the gradual elements that lead to children successfully generating sets and being classified as CP-knowers on the Give-N Task. Specifically, we test the claim that subset-knowers lack cardinal principle knowledge by separating children’s understanding of the cardinal principle from their ability to apply and implement counting procedures. We also ask when knowledge of Gelman & Gallistel’s (1978) other how-to-count principles emerge in development. We analyzed how often children violated the three how-to-count principles in a secondary analysis of Give-N data (N = 86). We found that children already have knowledge of the cardinal principle prior to becoming CP-knowers, and that understanding of the stable-order and word-object correspondence principles likely emerged earlier. These results suggest that gradual development may best characterize children’s acquisition of the counting principles, and that learning to coordinate all three principles represents an additional step beyond learning them individually.

Fourth Industrial Revolution and Geopolitics of Knowledge Production: The Question of Africa’s Place in the Global Space

Francis Fukuyama postulated that there are two powerful forces at work in human history. One, he calls, ‘the logic of modern science’ and the other, ‘the struggle for recognition’. I agree with Fukuyama that human developmental progression is propelled by these twin principles. It is my position that these principles have been the drivers of geopolitics. In this paper, I argue that, in addition, knowledge production is a major factor in geopolitics and that the Euro-American worldview has occupied the place of hegemony by reason of knowledge production. Africa has been denied having any form of epistemic tradition by the Euro-American world to sustain itself in the position of hegemony. In the era of Fourth Industrial Revolution, it will be antithetical for Africa to continue to adopt or consume technologies driven by Eurocentrism without projecting its contribution to the global space. Hence, using a critical hermeneutical approach, I contend that Africa needs to make a unique African contribution in the era of Fourth Industrial Revolution. It is Africa’s unique contribution that will guarantee Africa a place in geopolitics.

Systematic analysis of C. elegans embryo behavior reveals a stereotyped developmental progression and a rhythmic pattern of behavioral quiescence

Systematic analysis of rich behavioral recordings is being used to uncover how circuits encode complex behaviors. Here we apply the approach to embryos. What are the first embryonic behaviors and how do they evolve as early neurodevelopment ensues? To address these questions, we present a systematic description of behavioral maturation for Caenorhabditis elegans embryos. Posture libraries were derived from a genetically encoded motion capture suit imaged with light-sheet microscopy and annotated using custom semi-automated tracking software (Multiple Hypothesis Hypergraph Tracking; MHHT). Analysis of cell trajectories, postures, and behavioral motifs revealed a stereotyped developmental progression. Early movement is dominated by flipping between dorsal and ventral coiling, which gradually slows into a period of reduced motility. Late-stage embryos exhibit sinusoidal waves of dorsoventral bends, prolonged bouts of directed motion, and a rhythmic pattern of pausing, which we designate slow wave twitch (SWT). Synaptic transmission is required for late-stage motion but not for early flipping or the intervening inactive phase. A high-throughput behavioral assay and calcium imaging revealed that SWT is elicited by the rhythmic activity of a quiescence-promoting neuron (RIS). Similar periodic quiescent states are seen prenatally in divergent animals and may play an important role in promoting normal developmental outcomes.

The good, the bad, and the ugly: Evolutionary and pathological aspects of gene dosage alterations

Diploid organisms contain a maternal and a paternal genome complement that is thought to provide robustness and allow developmental progression despite genetic perturbations that occur in heterozygosity. However, changes affecting gene dosage from the chromosome down to the individual gene level possess a significant pathological potential and can lead to developmental disorders (DDs). This indicates that expression from a balanced gene complement is highly relevant for proper cellular and organismal function in eukaryotes. Paradoxically, gene and whole chromosome duplications are a principal driver of evolution, while heteromorphic sex chromosomes (XY and ZW) are naturally occurring aneuploidies important for sex determination. Here, we provide an overview of the biology of gene dosage at the crossroads between evolutionary benefit and pathogenicity during disease. We describe the buffering mechanisms and cellular responses to alterations, which could provide a common ground for the understanding of DDs caused by copy number alterations.

Developmental Patterning and Neurogenetic Gradients of Nurr1 Positive Neurons in the Rat Claustrum and Lateral Cortex

The claustrum is an enigmatic brain structure thought to be important for conscious sensations. Recent studies have focused on gene expression patterns, connectivity, and function of the claustrum, but relatively little is known about its development. Interestingly, claustrum-enriched genes, including the previously identified marker Nurr1, are not only expressed in the classical claustrum complex, but also embedded within lateral neocortical regions in rodents. Recent studies suggest that Nurr1 positive neurons in the lateral cortex share a highly conserved genetic expression pattern with claustrum neurons. Thus, we focus on the developmental progression and birth dating pattern of the claustrum and Nurr1 positive neurons in the lateral cortex. We comprehensively investigate the expression of Nurr1 at various stages of development in the rat and find that Nurr1 expression first appears as an elongated line along the anterior-posterior axis on embryonic day 13.5 (E13.5) and then gradually differentiates into multiple sub-regions during prenatal development. Previous birth dating studies of the claustrum have led to conflicting results, therefore, we combine 5-ethynyl-2′-deoxyuridine (EdU) labeling with in situ hybridization for Nurr1 to study birth dating patterns. We find that most dorsal endopiriform (DEn) neurons are born on E13.5 to E14.5. Ventral claustrum (vCL) and dorsal claustrum (dCL) are mainly born on E14.5 to E15.5. Nurr1 positive cortical deep layer neurons (dLn) and superficial layer neurons (sLn) are mainly born on E14.5 to E15.5 and E15.5 to E17.5, respectively. Finally, we identify ventral to dorsal and posterior to anterior neurogenetic gradients within vCL and DEn. Thus, our findings suggest that claustrum and Nurr1 positive neurons in the lateral cortex are born sequentially over several days of embryonic development and contribute toward charting the complex developmental pattern of the claustrum in rodents.

A single-cell transcriptome atlas of human early embryogenesis

The early window of human embryogenesis is largely a black box for developmental biologists. Here we probed the cellular diversity of 4- to 6-week human embryos when essentially all organs are just laid out. Based on over 100,000 single-cell transcriptomes, we generated a comprehensive atlas of 333 cell types that belong to 18 developmental systems, and identified hundreds of cell type specific markers as well as dynamic gene changes. Combined with data of other vertebrates, the rich information shed light on spatial patterning of axes, systemic temporal regulation of developmental progression and potential human-specific regulation. Our study provides a compendium of early progenitor cells of human organs, which can serve as the root of lineage analysis in organogenesis.

Conceptual replication and extension of the relation between the number line estimation task and mathematical competence across seven studies

A recent meta-analysis demonstrated the overall correlation between the number line estimation (NLE) task and children’s mathematical competence was r = .44 (positively recoded), and this relation increased with age. The goal of the current study was to conceptually replicate and extend these results by further synthesizing this correlation utilizing studies not present in the meta-analysis. Across seven studies, 954 participants, ranging from 3 to 11 years old (Age M = 6.02 years, SD = 1.57), the overall estimation-competence correlations were similar to those of the meta-analysis and ranged from r = −.40 to −.35. The current conceptual replication demonstrated that the meta-analysis captured a stable overall relation between performance on the NLE task and mathematical competence. However, the current study failed to replicate the same moderation of age group presented in the meta-analysis. Furthermore, the current study extended results by assessing the stability and predictive validity of the NLE task while controlling for covariates. Results suggested that the NLE task demonstrated poor stability and predictive validity in the seven samples present in this study. Thus, although concurrent relations replicated, the differential age moderation, lack of stability, and lack of predictive validity in these studies require a more nuanced approach to understanding the utility of the NLE task. Future research should focus on understanding the connection between children’s developmental progression and NLE measurement before further investigating the predictive and diagnostic importance of the task for broader mathematical competence.

EHMT2 suppresses the variation of transcriptional switches in the mouse embryo

EHMT2 is the main euchromatic H3K9 methyltransferase. Embryos with zygotic, or maternal mutation in the Ehmt2 gene exhibit variable developmental delay. To understand how EHMT2 prevents variable developmental delay we performed RNA sequencing of mutant and somite stage-matched normal embryos at 8.5–9.5 days of gestation. Using four-way comparisons between delayed and normal embryos we clarified what it takes to be normal and what it takes to develop. We identified differentially expressed genes, for example Hox genes that simply reflected the difference in developmental progression of wild type and the delayed mutant uterus-mate embryos. By comparing wild type and zygotic mutant embryos along the same developmental window we detected a role of EHMT2 in suppressing variation in the transcriptional switches. We identified transcription changes where precise switching during development occurred only in the normal but not in the mutant embryo. At the 6-somite stage, gastrulation-specific genes were not precisely switched off in the Ehmt2−/− zygotic mutant embryos, while genes involved in organ growth, connective tissue development, striated muscle development, muscle differentiation, and cartilage development were not precisely switched on. The Ehmt2mat−/+ maternal mutant embryos displayed high transcriptional variation consistent with their variable survival. Variable derepression of transcripts occurred dominantly in the maternally inherited allele. Transcription was normal in the parental haploinsufficient wild type embryos despite their delay, consistent with their good prospects. Global profiling of transposable elements revealed EHMT2 targeted DNA methylation and suppression at LTR repeats, mostly ERVKs. In Ehmt2−/− embryos, transcription over very long distances initiated from such misregulated ‘driver’ ERVK repeats, encompassing a multitude of misexpressed ‘passenger’ repeats. In summary, EHMT2 reduced transcriptional variation of developmental switch genes and developmentally switching repeat elements at the six-somite stage embryos. These findings establish EHMT2 as a suppressor of transcriptional and developmental variation at the transition between gastrulation and organ specification.

Nucleolar-based Dux repression is essential for 2-cell stage exit

Upon fertilisation, the mammalian embryo must switch from dependence on maternal transcripts to transcribing its own genome, and in mice involves the transient upregulation of MERVL transposons and MERVL-driven genes at the 2-cell stage. The mechanisms and requirement for MERVL and 2-cell (2C) gene upregulation are poorly understood. Moreover, this MERVL-driven transcriptional program must be rapidly shut off to allow 2-cell exit and developmental progression. Here, we report that robust ribosomal RNA (rRNA) synthesis and nucleolar maturation are essential for exit from the 2C state. 2C-like cells and 2-cell embryos show similar immature nucleoli with altered structure and reduced rRNA output. We reveal that nucleolar disruption via blocking Pol I activity or preventing nucleolar phase separation enhances conversion to a 2C-like state in embryonic stem cells (ESCs) by detachment of the MERVL activator Dux from the nucleolar surface. In embryos, nucleolar disruption prevents proper Dux silencing and leads to 2-4 cell arrest. Our findings reveal an intriguing link between rRNA synthesis, nucleolar maturation and gene repression during early development.