Advancing evolution: Bacteria break down gene silencer to express horizontally acquired genesGroisman, Eduardo A.; Choi, Jeongjoon
doi: 10.1002/bies.202300062pmid: 37533411
Horizontal gene transfer advances bacterial evolution. To benefit from horizontally acquired genes, enteric bacteria must overcome silencing caused when the widespread heat‐stable nucleoid structuring (H‐NS) protein binds to AT‐rich horizontally acquired genes. This ability had previously been ascribed to both anti‐silencing proteins outcompeting H‐NS for binding to AT‐rich DNA and RNA polymerase initiating transcription from alternative promoters. However, we now know that pathogenic Salmonella enterica serovar Typhimurium and commensal Escherichia coli break down H‐NS when this silencer is not bound to DNA. Curiously, both species use the same protease – Lon – to destroy H‐NS in distinct environments. Anti‐silencing proteins promote the expression of horizontally acquired genes without binding to them by displacing H‐NS from AT‐rich DNA, thus leaving H‐NS susceptible to proteolysis and decreasing H‐NS amounts overall. Conserved amino acid sequences in the Lon protease and H‐NS cleavage site suggest that diverse bacteria degrade H‐NS to exploit horizontally acquired genes.
The dynamic role of cohesin in maintaining human genome architectureAgarwal, Abhishek; Korsak, Sevastianos; Choudhury, Ashutosh; Plewczynski, Dariusz
doi: 10.1002/bies.202200240pmid: 37603403
Recent advances in genomic and imaging techniques have revealed the complex manner of organizing billions of base pairs of DNA necessary for maintaining their functionality and ensuring the proper expression of genetic information. The SMC proteins and cohesin complex primarily contribute to forming higher‐order chromatin structures, such as chromosomal territories, compartments, topologically associating domains (TADs) and chromatin loops anchored by CCCTC‐binding factor (CTCF) protein or other genome organizers. Cohesin plays a fundamental role in chromatin organization, gene expression and regulation. This review aims to describe the current understanding of the dynamic nature of the cohesin‐DNA complex and its dependence on cohesin for genome maintenance. We discuss the current 3C technique and numerous bioinformatics pipelines used to comprehend structural genomics and epigenetics focusing on the analysis of Cohesin‐centred interactions. We also incorporate our present comprehension of Loop Extrusion (LE) and insights from stochastic modelling.
Disruption of regulatory domains and novel transcripts as disease‐causing mechanismsAllou, Lila; Mundlos, Stefan
doi: 10.1002/bies.202300010pmid: 37381881
Deletions, duplications, insertions, inversions, and translocations, collectively called structural variations (SVs), affect more base pairs of the genome than any other sequence variant. The recent technological advancements in genome sequencing have enabled the discovery of tens of thousands of SVs per human genome. These SVs primarily affect non‐coding DNA sequences, but the difficulties in interpreting their impact limit our understanding of human disease etiology. The functional annotation of non‐coding DNA sequences and methodologies to characterize their three‐dimensional (3D) organization in the nucleus have greatly expanded our understanding of the basic mechanisms underlying gene regulation, thereby improving the interpretation of SVs for their pathogenic impact. Here, we discuss the various mechanisms by which SVs can result in altered gene regulation and how these mechanisms can result in rare genetic disorders. Beyond changing gene expression, SVs can produce novel gene‐intergenic fusion transcripts at the SV breakpoints.
Epromoters are new players in the regulatory landscape with potential pleiotropic rolesMalfait, Juliette; Wan, Jing; Spicuglia, Salvatore
doi: 10.1002/bies.202300012pmid: 37246247
Precise spatiotemporal control of gene expression during normal development and cell differentiation is achieved by the combined action of proximal (promoters) and distal (enhancers) cis‐regulatory elements. Recent studies have reported that a subset of promoters, termed Epromoters, works also as enhancers to regulate distal genes. This new paradigm opened novel questions regarding the complexity of our genome and raises the possibility that genetic variation within Epromoters has pleiotropic effects on various physiological and pathological traits by differentially impacting multiple proximal and distal genes. Here, we discuss the different observations pointing to an important role of Epromoters in the regulatory landscape and summarize the evidence supporting a pleiotropic impact of these elements in disease. We further hypothesize that Epromoter might represent a major contributor to phenotypic variation and disease.
Understanding fundamental principles of enhancer biology at a model locusKassouf, Mira; Ford, Seren; Blayney, Joseph; Higgs, Doug
doi: 10.1002/bies.202300047pmid: 37404089
Despite ever‐increasing accumulation of genomic data, the fundamental question of how individual genes are switched on during development, lineage‐specification and differentiation is not fully answered. It is widely accepted that this involves the interaction between at least three fundamental regulatory elements: enhancers, promoters and insulators. Enhancers contain transcription factor binding sites which are bound by transcription factors (TFs) and co‐factors expressed during cell fate decisions and maintain imposed patterns of activation, at least in part, via their epigenetic modification. This information is transferred from enhancers to their cognate promoters often by coming into close physical proximity to form a ‘transcriptional hub’ containing a high concentration of TFs and co‐factors. The mechanisms underlying these stages of transcriptional activation are not fully explained. This review focuses on how enhancers and promoters are activated during differentiation and how multiple enhancers work together to regulate gene expression. We illustrate the currently understood principles of how mammalian enhancers work and how they may be perturbed in enhanceropathies using expression of the α‐globin gene cluster during erythropoiesis, as a model.
May the force be with you: Nuclear condensates function beyond transcription controlNegri, Maria Luce; D'Annunzio, Sarah; Vitali, Giulia; Zippo, Alessio
doi: 10.1002/bies.202300075pmid: 37530178
Over the past decade, research has revealed biomolecular condensates' relevance in diverse cellular functions. Through a phase separation process, they concentrate macromolecules in subcompartments shaping the cellular organization and physiology. In the nucleus, biomolecular condensates assemble relevant biomolecules that orchestrate gene expression. We here hypothesize that chromatin condensates can also modulate the nongenetic functions of the genome, including the nuclear mechanical properties. The importance of chromatin condensates is supported by the genetic evidence indicating that mutations in their members are causative of a group of rare Mendelian diseases named chromatinopathies (CPs). Despite a broad spectrum of clinical features and the perturbations of the epigenetic machinery characterizing the CPs, recent findings highlighted negligible changes in gene expression. These data argue in favor of possible noncanonical functions of chromatin condensates in regulating the genome's spatial organization and, consequently, the nuclear mechanics. In this review, we discuss how condensates may impact nuclear mechanical properties, thus affecting the cellular response to mechanical cues and, eventually, cell fate and identity.