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Eukaryotic gene regulation is mediated by cis -regulatory elements, which are embedded within the vast non-coding genomic space and recognized by the transcription factors in a sequence- and context-dependent manner. A large proportion of eukaryotic genomes, including at least half of the human genome, are composed of transposable elements (TEs), which in their ancestral form carried their own cis -regulatory sequences able to exploit the host trans environment to promote TE transcription and facilitate transposition. Although not all present-day TE copies have retained this regulatory function, the preexisting regulatory potential of TEs can provide a rich source of cis -regulatory innovation for the host. Here, we review recent evidence documenting diverse contributions of TE sequences to gene regulation by functioning as enhancers, promoters, silencers and boundary elements. We discuss how TE-derived enhancer sequences can rapidly facilitate changes in existing gene regulatory networks and mediate species- and cell-type-specific regulatory innovations, and we postulate a unique contribution of TEs to species-specific gene expression divergence in pluripotency and early embryogenesis. With advances in genome-wide technologies and analyses, systematic investigation of TEs' cis -regulatory potential is now possible and our understanding of the biological impact of genomic TEs is increasing. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

A major shift in our understanding of genome regulation has emerged recently. It is now apparent that the majority of cellular transcripts do not code for proteins, and many of them are long noncoding RNAs (lncRNAs). Increasingly, studies suggest that lncRNAs regulate gene expression through diverse mechanisms. We review emerging mechanistic views of lncRNAs in gene regulation in the cell nucleus. We discuss the functional interactions that lncRNAs establish with other molecules as well as the relationship between lncRNA transcription and function. While some of these mechanisms are specific to lncRNAs, others might be shared with other types of genes.

Methylation of adenosines at the N6 position (m6A) is a dynamic and abundant epitranscriptomic mark that regulates critical aspects of eukaryotic RNA metabolism in numerous biological processes. The RNA methyltransferases METTL3 and METTL14 are components of a multisubunit m6A writer complex whose enzymatic activity is substantially higher than the activities of METTL3 or METTL14 alone. The molecular mechanism underpinning this synergistic effect is poorly understood. Here we report the crystal structure of the catalytic core of the human m6A writer complex comprising METTL3 and METTL14. The structure reveals the heterodimeric architecture of the complex and donor substrate binding by METTL3. Structure-guided mutagenesis indicates that METTL3 is the catalytic subunit of the complex, whereas METTL14 has a degenerate active site and plays non-catalytic roles in maintaining complex integrity and substrate RNA binding. These studies illuminate the molecular mechanism and evolutionary history of eukaryotic m6A modification in post-transcriptional genome regulation.

Key messageCytokinins are a class of phytohormone that participate in the regulation of the plant growth, development, and stress response. In this review, the potential regulating mechanism during plant growth and stress response are discussed.Cytokinins are a class of phytohormone that participate in the regulation of plant growth, physiological activities, and yield. Cytokinins also play a key role in response to abiotic stresses, such as drought, salt and high or low temperature. Through the signal transduction pathway, cytokinins interact with various transcription factors via a series of phosphorylation cascades to regulate cytokinin-target gene expression. In this review, we systematically summarize the biosynthesis and metabolism of cytokinins, cytokinin signaling, and associated gene regulation, and highlight the function of cytokinins during plant development and resistance to abiotic stress. We also focus on the importance of crosstalk between cytokinins and other classes of phytohormones, including auxin, ethylene, strigolactone, and gibberellin. Our aim is to provide a comprehensive overview of recent findings on the mechanisms by which cytokinins act as central regulators of plant development and stress reactions, and highlight topics for future research.

Across bacteria, RNA binding proteins, such as Hfq, often play a key role in facilitating post-transcriptional regulation by chaperoning interactions between small regulatory RNAs (sRNAs) and their mRNA targets. , a problematic gram-negative bacterial pathogen, produces over a hundred sRNAs, of which only a few have experimentally validated mRNA targets. While previous studies have identified as a candidate essential gene in the model multidrug-resistant strain AB5075, the role of Hfq in mediating the regulatory effects of sRNAs remains largely unexplored. Here, we use RIL-seq to identify Hfq-associated sRNA-mRNA interaction partners in strain AB5075. Our results indicate that Hfq coordinates a robust network of RNA-RNA interactions. We detected RNA interactions with 98 distinct sRNA species, including nearly 40 previously undescribed sRNAs. The results further indicate that utilizes sRNAs to regulate the expression of numerous transcripts that encode virulence factors and antibiotic resistance determinants. Collectively, our study provides new insights into the regulatory potential for dozens of sRNAs in and highlights the importance of post-transcriptional regulation in this emerging pathogen.IMPORTANCE represents a burgeoning threat to human health and consistently ranks as a critical pathogen by the World Health Organization due to extensive antimicrobial resistance among clinical isolates. While much effort has focused on understanding how acquires antimicrobial resistance traits, our knowledge of key processes governing gene expression in this organism is lacking. In particular, very little is known regarding post-transcriptional regulation in . Here, we demonstrate that Hfq, a highly conserved RNA chaperone, coordinates the regulatory activities for nearly 100 small regulatory RNAs (sRNAs), including many that have not been described before. We also find that several Hfq-associated sRNAs directly regulate mRNA transcripts, which encode antibiotic resistance determinants and virulence factors. Collectively, our study provides evidence for the existence of a complex post-transcriptional regulatory network in and offers new insights into how the organism uses Hfq and sRNAs to coordinate gene expression.

Osteoarthritis (OA) is a painful and debilitating condition of synovial joints without any disease-modifying therapies [A. M. Valdes, T. D. Spector, Nat. Rev. Rheumatol. 7, 23–32 (2011)]. We previously identified mechanosensitive PIEZO channels, PIEZO1 and PIEZO2, both expressed in articular cartilage, to function in chondrocyte mechanotransduction in response to injury [W. Lee et al., Proc. Natl. Acad. Sci. U.S.A. 111, E5114–E5122 (2014); W. Lee, F. Guilak, W. Liedtke, Curr. Top. Membr. 79, 263–273 (2017)]. We therefore asked whether interleukin-1–mediated inflammatory signaling, as occurs in OA, influences Piezo gene expression and channel function, thus indicative of maladaptive reprogramming that can be rationally targeted. Primary porcine chondrocyte culture and human osteoarthritic cartilage tissue were studied. We found that interleukin-1α (IL-1α) up-regulated Piezo1 in porcine chondrocytes. Piezo1 expression was significantly increased in human osteoarthritic cartilage. Increased Piezo1 expression in chondrocytes resulted in a feed-forward pathomechanism whereby increased function of Piezo1 induced excess intracellular Ca2+ at baseline and in response to mechanical deformation. Elevated resting state Ca2+ in turn rarefied the F-actin cytoskeleton and amplified mechanically induced deformation microtrauma. As intracellular substrates of this OA-related inflammatory pathomechanism, in porcine articular chondrocytes exposed to IL-1α, we discovered that enhanced Piezo1 expression depended on p38 MAP-kinase and transcription factors HNF4 and ATF2/CREBP1. CREBP1 directly bound to the proximal PIEZO1 gene promoter. Taken together, these signaling and genetic reprogramming events represent a detrimental Ca2+-driven feed-forward mechanism that can be rationally targeted to stem the progression of OA.

Joint profiling of chromatin accessibility and gene expression in individual cells provides an opportunity to decipher enhancer-driven gene regulatory networks (GRNs). Here we present a method for the inference of enhancer-driven GRNs, called SCENIC+. SCENIC+ predicts genomic enhancers along with candidate upstream transcription factors (TFs) and links these enhancers to candidate target genes. To improve both recall and precision of TF identification, we curated and clustered a motif collection with more than 30,000 motifs. We benchmarked SCENIC+ on diverse datasets from different species, including human peripheral blood mononuclear cells, ENCODE cell lines, melanoma cell states and Drosophila retinal development. Next, we exploit SCENIC+ predictions to study conserved TFs, enhancers and GRNs between human and mouse cell types in the cerebral cortex. Finally, we use SCENIC+ to study the dynamics of gene regulation along differentiation trajectories and the effect of TF perturbations on cell state. SCENIC+ is available at scenicplus.readthedocs.io . SCENIC+ is a comprehensive toolbox for inferring and analyzing enhancer-driven gene regulatory networks using single-cell multiomic data.