The proper activities of enhancers and gene promoters are essential for coordinated transcription within a cell. Although diverse methodologies have been developed to identify enhancers and ...promoters, most have tacitly assumed that these elements are distinct. However, studies have unexpectedly shown that regulatory elements may have both enhancer and promoter functions. Here we review these results, focusing on the factors that determine the promoter and/or enhancer activity of regulatory elements. We discuss emerging models that define regulatory elements by accessible DNA and their non-mutually-exclusive abilities to drive transcription initiation (promoter activity) and/or to enhance transcription at other such regions (enhancer activity).
Highlights • Recent results challenge the notion that promoters and enhancers are distinct entities. • Enhancers can independently work as promoters. • Gene promoters can have enhancer activity. • ...The primary function of a regulatory element is context dependent. • We propose a unified model of regulatory elements.
During genome replication, parental histones are recycled to newly replicated DNA with their posttranslational modifications (PTMs). It remains unknown whether sister chromatids inherit modified ...histones evenly. Here, we measured histone PTM partition to sister chromatids in embryonic stem cells. We found that parental histones H3-H4 segregate to both daughter DNA strands with a weak leading strand bias, skewing partition at topologically associating domain (TAD) borders and enhancers proximal to replication initiation zones. Segregation of parental histones to the leading strand increased markedly in cells with histone-binding mutations in MCM2, part of the replicative helicase, exacerbating histone PTM sister chromatid asymmetry. This work reveals how histones are inherited to sister chromatids and identifies a mechanism for how symmetric cell division is ensured by the replication machinery.
In this article, we use critical policy analysis to explore how Nordic national policies express the purposes and positions of civil society organizations (CSOs) in efforts to prevent violent ...extremism (PVE). Furthermore, we analyze how the problem of extremism is constituted by this involvement. While the paper finds that CSOs are positioned as important actors, much due to their autonomous character and their legitimacy among target groups, the purposes and measures suggested in policy may harm their voluntary character. Furthermore, the analysis shows that the problem with extremism is mainly placed within the realms of religious communities and thereby runs the risk of (re)producing ideas of Islam as an extreme, anti-democratic religion. In extension, the well-intended involvement of CSOs in policy to prevent violent extremism might, in its current form, jeopardize the democratic rights of freedom of organization and freedom of speech and religion.
National approaches to prevent terrorism, extremism, and radicalisation have changed considerably over the last decades. Previous studies mapping these changes have primarily relied on empirical ...analyses of formal policy and political processes. This case-study of Sweden takes an alternative route, and analyses a dataset of 1405 Swedish newspaper articles (1985-2019) using a new institutional theory and social movement theory framework. Therethrough, the paper is able to provide new insights into the emergence and development of an institutional issue field concerned with the prevention of terrorism, extremism, and radicalisation. More specifically, the paper highlights the unstable, fragmented, dynamic and contested character of the field's development. Frames containing the problems and solutions considered most important during each of the field's five stages are identified, and the subsequent institutional and organisational consequences are discussed. The paper also considers how terror attacks and other extremism-related events impact the institutionalisation and alternation of dominant frames, and identifies the translation and development of an inclusive vocabulary as pivotal to mobilising a broad and diverse set of actors to co-produce preventive efforts.
Despite the growing importance of local action to counter violent extremism (CVE), empirical research on the local organization and management of CVE is scarce, especially regarding public ...administrators' strategic work to translate policies and recommendations into frontline practice. Based mainly on ethnographic data and departing from new institutional theory, the paper refines our understanding of the symbolic, material, and relational work used to translate a diverse flow of ideas into concrete action in diverse institutional settings. Due to the institutional complexity, the cultural skill of the local CVE coordinator is identified as pivotal to successfully legitimizing and implementing CVE efforts.
Abstract
Transposable elements are an abundant source of transcription factor binding sites, and favorable genomic integration may lead to their recruitment by the host genome for gene regulatory ...functions. However, it is unclear how frequent co-option of transposable elements as regulatory elements is, to which regulatory programs they contribute and how they compare to regulatory elements devoid of transposable elements. Here, we report a transcription initiation-centric, in-depth characterization of the transposon-derived regulatory landscape of mouse embryonic stem cells. We demonstrate that a substantial number of transposable element insertions, in particular endogenous retroviral elements, are associated with open chromatin regions that are divergently transcribed into unstable RNAs in a cell-type specific manner, and that these elements contribute to a sizable proportion of active enhancers and gene promoters. We further show that transposon subfamilies contribute differently and distinctly to the pluripotency regulatory program through their repertoires of transcription factor binding site sequences, shedding light on the formation of regulatory programs and the origins of regulatory elements.
Transcriptional regulation is tightly coupled with chromosomal positioning and three-dimensional chromatin architecture. However, it is unclear what proportion of transcriptional activity is ...reflecting such organisation, how much can be informed by RNA expression alone and how this impacts disease. Here, we develop a computational transcriptional decomposition approach separating the proportion of expression associated with genome organisation from independent effects not directly related to genomic positioning. We show that positionally attributable expression accounts for a considerable proportion of total levels and is highly informative of topological associating domain activities and organisation, revealing boundaries and chromatin compartments. Furthermore, expression data alone accurately predict individual enhancer-promoter interactions, drawing features from expression strength, stabilities, insulation and distance. We characterise predictions in 76 human cell types, observing extensive sharing of domains, yet highly cell-type-specific enhancer-promoter interactions and strong enrichments in relevant trait-associated variants. Overall, our work demonstrates a close relationship between transcription and chromatin architecture.
5'-end sequencing assays, and Cap Analysis of Gene Expression (CAGE) in particular, have been instrumental in studying transcriptional regulation. 5'-end methods provide genome-wide maps of ...transcription start sites (TSSs) with base pair resolution. Because active enhancers often feature bidirectional TSSs, such data can also be used to predict enhancer candidates. The current availability of mature and comprehensive computational tools for the analysis of 5'-end data is limited, preventing efficient analysis of new and existing 5'-end data.
We present CAGEfightR, a framework for analysis of CAGE and other 5'-end data implemented as an R/Bioconductor-package. CAGEfightR can import data from BigWig files and allows for fast and memory efficient prediction and analysis of TSSs and enhancers. Downstream analyses include quantification, normalization, annotation with transcript and gene models, TSS shape statistics, linking TSSs to enhancers via co-expression, identification of enhancer clusters, and genome-browser style visualization. While built to analyze CAGE data, we demonstrate the utility of CAGEfightR in analyzing nascent RNA 5'-data (PRO-Cap). CAGEfightR is implemented using standard Bioconductor classes, making it easy to learn, use and combine with other Bioconductor packages, for example popular differential expression tools such as limma, DESeq2 and edgeR.
CAGEfightR provides a single, scalable and easy-to-use framework for comprehensive downstream analysis of 5'-end data. CAGEfightR is designed to be interoperable with other Bioconductor packages, thereby unlocking hundreds of mature transcriptomic analysis tools for 5'-end data. CAGEfightR is freely available via Bioconductor: bioconductor.org/packages/CAGEfightR .
The genomes of higher organisms are packaged in nucleosomes with functional histone modifications. Until now, genome-wide nucleosome and histone modification studies have focused on transcription ...start sites (TSSs) where nucleosomes in RNA polymerase II (RNAPII) occupied genes are well positioned and have histone modifications that are characteristic of expression status. Using public data, we here show that there is a higher nucleosome-positioning signal in internal human exons and that this positioning is independent of expression. We observed a similarly strong nucleosome-positioning signal in internal exons of Caenorhabditis elegans. Among the 38 histone modifications analyzed in man, H3K36me3, H3K79me1, H2BK5me1, H3K27me1, H3K27me2, and H3K27me3 had evidently higher signals in internal exons than in the following introns and were clearly related to exon expression. These observations are suggestive of roles in splicing. Thus, exons are not only characterized by their coding capacity, but also by their nucleosome organization, which seems evolutionarily conserved since it is present in both primates and nematodes.
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