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Chromosome structure in mammals is thought to regulate transcription by modulating three-dimensional interactions between enhancers and promoters, notably through CTCF-mediated loops and topologically associating domains (TADs) 1 – 4 . However, how chromosome interactions are actually translated into transcriptional outputs remains unclear. Here, to address this question, we use an assay to position an enhancer at large numbers of densely spaced chromosomal locations relative to a fixed promoter, and measure promoter output and interactions within a genomic region with minimal regulatory and structural complexity. A quantitative analysis of hundreds of cell lines reveals that the transcriptional effect of an enhancer depends on its contact probabilities with the promoter through a nonlinear relationship. Mathematical modelling suggests that nonlinearity might arise from transient enhancer–promoter interactions being translated into slower promoter bursting dynamics in individual cells, therefore uncoupling the temporal dynamics of interactions from those of transcription. This uncovers a potential mechanism of how distal enhancers act from large genomic distances, and of how topologically associating domain boundaries block distal enhancers. Finally, we show that enhancer strength also determines absolute transcription levels as well as the sensitivity of a promoter to CTCF-mediated transcriptional insulation. Our measurements establish general principles for the context-dependent role of chromosome structure in long-range transcriptional regulation. The transcriptional effect of an enhancer depends on its contact probabilities with the promoter through a nonlinear relationship, and enhancer strength determines absolute transcription levels as well as the sensitivity of a promoter to CTCF-mediated transcriptional insulation.

Chromatin remodeling provides essential transcriptional regulation for all biological processes. In Caenorhabditis elegans , the chromatin remodeler LET-418, a homolog of the human Mi-2β protein, plays a critical role in regulating development, organogenesis, tissue maintenance, stress resistance and lifespan. LET-418 is part of several chromatin remodeling complexes and contributes significantly to the balance between growth and defense mechanisms, yet its target genes remain unclear. Using DNA methylation profiling, we identified genomic binding sites and associated target genes of LET-418 and its MEC-complex-specific interactor MEP-1 in the intestine. Consistent with their presence in the same complex, the two proteins shared more than half of their target genes. Functional analysis revealed that LET-418 and MEP-1 target genes are highly active in the intestine and are involved in repressing innate immune responses, including the intracellular pathogen response (IPR). Consistently, in let-418 mutants, IPR-induced genes, such as pals-5 or pals-2 are strongly upregulated, in a manner dependent on ZIP-1, a major transcription factor for IPR. Additionally, we found pathogen levels of the natural intracellular intestinal pathogen Nematocida parisii significantly reduced in let-418 mutants, supporting the observation of increased IPR in this mutant. Altogether, these findings reveal a crucial role for LET-418 as a modulator of the IPR, aligning with its role in maintaining the balance between development and defense.

Transcriptional enhancers must locate target genes with precision. In mammals, topologically associating domains (TADs) guide this process, but the C. elegans genome lacks such organization despite containing over 30,000 putative enhancers. Using high-resolution Hi-C, we identify distinct 3D chromatin structures around active enhancers, termed fountains. These ~38 kb cohesin-dependent structures are unique to active enhancers and enriched for topoisomerases and negatively supercoiled DNA, indicating topological stress. Disrupting cohesin collapses fountains and leads to transcriptional upregulation of nearby genes, suggesting fountains act as spatial repressors controlling enhancer–promoter communication. This repression preferentially affects neuronal genes, including skn-1/Nrf , which changes isoform usage upon cohesin loss in ASI neurons. Cohesin cleavage also alters nematode movement and foraging behavior, linking 3D genome architecture to neural function and behavior. Thus, fountains represent a distinctive chromatin feature that may ensure enhancer specificity in a TAD-less genome. In the nematode C. elegans, cohesin creates specifically at active enhancers chromatin 3D structures named fountains. Cohesin artificial cleavage disrupts fountains and changes neuronal gene expression, function and animal behavior.

At first glance, Public Sector Innovation (PSI) Labs are gaining prominence within academic literature, the European Union (EU) and beyond. However, because of the relative newness and conceptual ambiguity of this concept, the exact contribution of these labs to theory and practice is still unclear. In addition, most research has been looking at case studies. This publication breaks new ground by elaborating on the concept and also by looking at the perception of these labs in different contexts, by comparing multiple labs in multiple countries. In doing so, we raised the question: ‘What is the perceived added value of Public Sector Innovation labs for further developing theory as well as for society?’ In order to answer this question, by way of an experiment, we combined theoretical research together with focus groups with members of the EU funded project Multi Disciplinary Innovation for Social Change (SHIINE) in combination with questionnaires to selected PSI labs, thus providing us with rich data. Our experimental methodology uncovered a conceptual bias that is probably existent in similar studies and needs to be acknowledged more. In addition, we found that PSI labs have developed over time into an amalgam of two competing concepts. To conclude, we believe that the specific potential of PSI labs as an internal space for innovation within institutions is underutilised. We believe this could be improved by acknowledging the specific aim of PSI labs in a co-creative setting between relevant stakeholders, such as Higher Education Institutions (HEIs).

Some of the poetry that medievalists study today was jotted in the margins of medieval manuscripts by scholars taking a break from their day job. Albrecht Classen does likewise today, serving readers of his criticism as a helpful guide in part because he refuses to forget he is a poet.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Both environmental and genetic factors are thought to contribute to the pathogenesis of PD. Although several genes linked to rare familial PD have been identified, endogenous risk factors for sporadic PD, which account for the majority of PD cases, remain largely unknown. Genome-wide association studies have identified many single nucleotide polymorphisms associated with sporadic PD in neurodevelopmental genes including the transcription factor p48/ptf1a. Here we investigate whether p48 plays a role in the survival of DA neurons in Drosophila melanogaster and Caenorhabditis elegans. We show that a Drosophila p48 homolog, 48-related-2 (Fer2), is expressed in and required for the development and survival of DA neurons in the protocerebral anterior medial (PAM) cluster. Loss of Fer2 expression in adulthood causes progressive PAM neuron degeneration in aging flies along with mitochondrial dysfunction and elevated reactive oxygen species (ROS) production, leading to the progressive locomotor deficits. The oxidative stress challenge upregulates Fer2 expression and exacerbates the PAM neuron degeneration in Fer2 loss-of-function mutants. hlh-13, the worm homolog of p48, is also expressed in DA neurons. Unlike the fly counterpart, hlh-13 loss-of-function does not impair development or survival of DA neurons under normal growth conditions. Yet, similar to Fer2, hlh-13 expression is upregulated upon an acute oxidative challenge and is required for the survival of DA neurons under oxidative stress in adult worms. Taken together, our results indicate that p48 homologs share a role in protecting DA neurons from oxidative stress and degeneration, and suggest that loss-of-function of p48 homologs in flies and worms provides novel tools to study gene-environmental interactions affecting DA neuron survival.

The structural maintenance of chromosome (SMC) complexes—cohesin and condensins—are crucial for chromosome separation and compaction during cell division. During the interphase, mammalian cohesins additionally fold the genome into loops and domains. Here we show that, in Caenorhabditis elegans , a species with holocentric chromosomes, condensin I is the primary, long-range loop extruder. The loss of condensin I and its X-specific variant, condensin I DC , leads to genome-wide decompaction, chromosome mixing and disappearance of X-specific topologically associating domains, while reinforcing fine-scale epigenomic compartments. In addition, condensin I/I DC inactivation led to the upregulation of X-linked genes and unveiled nuclear bodies grouping together binding sites for the X-targeting loading complex of condensin I DC . C. elegans condensin I/I DC thus uniquely organizes holocentric interphase chromosomes, akin to cohesin in mammals, as well as regulates X-chromosome gene expression. Inactivation of somatic SMC complexes in Caenorhabditis elegans shows that condensin I is the major long-range genome loop extruder, while cohesin forms small loops. Inactivation of cohesin, condensin II and condensin I/I DC causes minor transcriptional changes in autosomes.

Abstract Differential gene expression across cell types underlies development and cell physiology in multicellular organisms. Caenorhabditis elegans is a powerful, extensively used model to address these biological questions. A remaining bottleneck relates to the difficulty to obtain comprehensive tissue-specific gene transcription data, since available methods are still challenging to execute and/or require large worm populations. Here, we introduce the RNA Polymerase DamID (RAPID) approach, in which the Dam methyltransferase is fused to a ubiquitous RNA polymerase subunit to create transcriptional footprints via methyl marks on the DNA of transcribed genes. To validate the method, we determined the polymerase footprints in whole animals, in sorted embryonic blastomeres and in different tissues from intact young adults by driving tissue-specific Dam fusion expression. We obtained meaningful transcriptional footprints in line with RNA-sequencing (RNA-seq) studies in whole animals or specific tissues. To challenge the sensitivity of RAPID and demonstrate its utility to determine novel tissue-specific transcriptional profiles, we determined the transcriptional footprints of the pair of XXX neuroendocrine cells, representing 0.2% of the somatic cell content of the animals. We identified 3901 candidate genes with putatively active transcription in XXX cells, including the few previously known markers for these cells. Using transcriptional reporters for a subset of new hits, we confirmed that the majority of them were expressed in XXX cells and identified novel XXX-specific markers. Taken together, our work establishes RAPID as a valid method for the determination of RNA polymerase footprints in specific tissues of C. elegans without the need for cell sorting or RNA tagging.

We report the reproductive strategy of the nematode Mesorhabditis belari. This species produces only 9% males, whose sperm is necessary to fertilize and activate the eggs. However, most of the fertilized eggs develop without using the sperm DNA and produce female individuals. Only in 9% of eggs is the male DNA utilized, producing sons.We found that mixing of parental genomes only gives rise to males because the Y-bearing sperm of males are much more competent than the X-bearing sperm for penetrating the eggs. In this previously unrecognized strategy, asexual females produce few sexual males whose genes never reenter the female pool. Here, production of males is of interest only if sons are more likely to mate with their sisters. Using game theory, we show that in this context, the production of 9% males by M. belari females is an evolutionary stable strategy.

Stable cell fate is an essential feature for multicellular organisms in which individual cells achieve specialized functions. Caenorhabditis elegans is a great model to analyze the determinants of cell fate stability because of its invariant lineage. We present a tractable cell fate challenge system that uses the induction of fate-specifying transcription factors. We show that wild-type differentiated animals are highly resistant to fate challenge. Removal of heterochromatin marks showed marked differences: the absence of histone 3 lysine 9 methylation (H3K9) has no effect on fate stability, whereas Polycomb homolog mes-2 mutants lacking H3K27 methylation terminally arrest larval development upon fate challenge. Unexpectedly, the arrest correlated with widespread cell proliferation rather than transdifferentiation. Using a candidate RNAi larval arrest-rescue screen, we show that the LIN-12 Notch pathway is essential for hyperplasia induction. Moreover, Notch signaling appears downstream of food-sensing pathways, as dauers and first larval stage diapause animals are resistant to fate challenge. Our results demonstrate an equilibrium between proliferation and differentiation regulated by Polycomb and Notch signaling in the soma during the nematode life cycle.