Histone posttranslational modifications control eukaryotic gene expression and regulate many biological processes including immunity. Pathogens alter host epigenetic control to aid pathogenesis. We ...find that the intracellular bacterial pathogen Legionella pneumophila uses a Dot/Icm type IV secreted effector, RomA, to uniquely modify the host chromatin landscape. RomA, a SET domain-containing methyltransferase, trimethylates K14 of histone H3, a histone mark not previously described in mammals. RomA localizes to the infected cell nucleus where it promotes a burst of H3K14 methylation and consequently decreases H3K14 acetylation, an activating histone mark, to repress host gene expression. ChIP-seq analysis identified 4,870 H3K14 methylated promoter regions, including innate immune genes. Significantly reduced replication of a RomA-deleted strain in host cells was trans-complemented by wild-type, but not by catalytically inactive, RomA. Thus, a secreted L. pneumophila effector targets the host cell nucleus and modifies histones to repress gene expression and promote efficient intracellular replication.
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► Upon infection, L. pneumophila secretes RomA, a SET domain-containing methyltransferase ► RomA triggers H3K14 trimethylation, causing a switch from gene activation to repression ► ChIP-seq identified 4,870 H3K14 methylated promoter regions, including innate immune genes ► RomA SET domain is required for efficient intracellular replication of L. pneumophila
Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of Polycomb repressive complex 2 (PRC2), has attracted broad research attention in the past few years because of its involvement in the ...development and maintenance of many types of cancer and the use of specific EZH2 inhibitors in clinical trials. Several observations show that PRC2 can have both oncogenic and tumour-suppressive functions. We propose that these apparently opposing roles of PRC2 in cancer are a consequence of the molecular function of the complex in maintaining, rather than specifying, the transcriptional repression state of its several thousand target genes.
Topoisomerases introduce transient DNA breaks to relax supercoiled DNA, remove catenanes and enable chromosome segregation. Human cells encode six topoisomerases (TOP1, TOP1mt, TOP2α, TOP2β, TOP3α ...and TOP3β), which act on a broad range of DNA and RNA substrates at the nuclear and mitochondrial genomes. Their catalytic intermediates, the topoisomerase cleavage complexes (TOPcc), are therapeutic targets of various anticancer drugs. TOPcc can also form on damaged DNA during replication and transcription, and engage specific repair pathways, such as those mediated by tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2 and by endonucleases (MRE11, XPF-ERCC1 and MUS81). Here, we review the roles of topoisomerases in mediating chromatin dynamics, transcription, replication, DNA damage repair and genomic stability, and discuss how deregulation of topoisomerases can cause neurodegenerative diseases, immune disorders and cancer.
Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioural processes in organisms. These cell-autonomous clocks are composed of a transcription-translation-based ...autoregulatory feedback loop. With the development of next-generation sequencing approaches, biochemical and genomic insights into circadian function have recently come into focus. Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling. The genomic targets of circadian clocks are pervasive and are intimately linked to the regulation of metabolism, cell growth and physiology.
We describe the identification and characterization of circular intronic long noncoding RNAs in human cells, which accumulate owing to a failure in debranching. The formation of such circular ...intronic RNAs (ciRNAs) can be recapitulated using expression vectors, and their processing depends on a consensus motif containing a 7 nt GU-rich element near the 5′ splice site and an 11 nt C-rich element close to the branchpoint site. In addition, we show that ciRNAs are abundant in the nucleus and have little enrichment for microRNA target sites. Importantly, knockdown of ciRNAs led to the reduced expression of their parent genes. One abundant such RNA, ci-ankrd52, largely accumulates to its sites of transcription, associates with elongation Pol II machinery, and acts as a positive regulator of Pol II transcription. This study thus suggests a cis-regulatory role of noncoding intronic transcripts on their parent coding genes.
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•Circular intronic RNAs accumulate in human cells owing to escape from debranching•Their processing depends on RNA motifs near 5′ splice site and branchpoint•ciRNAs regulate parent gene expression by modulating elongation Pol II activity
The glucocorticoid receptor (GR) is a constitutively expressed transcriptional regulatory factor (TRF) that controls many distinct gene networks, each uniquely determined by particular cellular and ...physiological contexts. The precision of GR-mediated responses seems to depend on combinatorial, context-specific assembly of GR-nucleated transcription regulatory complexes at genomic response elements. In turn, evidence suggests that context-driven plasticity is conferred by the integration of multiple signals, each serving as an allosteric effector of GR conformation, a key determinant of regulatory complex composition and activity. This structural and mechanistic perspective on GR regulatory specificity is likely to extend to other eukaryotic TRFs.
Advances in genomics technology have provided the means to probe myriad chromatin interactions at unprecedented spatial and temporal resolution. This has led to a profound understanding of nucleosome ...organization within the genome, revealing that nucleosomes are highly dynamic. Nucleosome dynamics are governed by a complex interplay of histone composition, histone post-translational modifications, nucleosome occupancy and positioning within chromatin, which are influenced by numerous regulatory factors, including general regulatory factors, chromatin remodellers, chaperones and polymerases. It is now known that these dynamics regulate diverse cellular processes ranging from gene transcription to DNA replication and repair.
In cancer, the epithelial-to-mesenchymal transition (EMT) is associated with tumour stemness, metastasis and resistance to therapy. It has recently been proposed that, rather than being a binary ...process, EMT occurs through distinct intermediate states. However, there is no direct in vivo evidence for this idea. Here we screen a large panel of cell surface markers in skin and mammary primary tumours, and identify the existence of multiple tumour subpopulations associated with different EMT stages: from epithelial to completely mesenchymal states, passing through intermediate hybrid states. Although all EMT subpopulations presented similar tumour-propagating cell capacity, they displayed differences in cellular plasticity, invasiveness and metastatic potential. Their transcriptional and epigenetic landscapes identify the underlying gene regulatory networks, transcription factors and signalling pathways that control these different EMT transition states. Finally, these tumour subpopulations are localized in different niches that differentially regulate EMT transition states.
Long intervening noncoding RNAs (lincRNAs) are transcribed from thousands of loci in mammalian genomes and might play widespread roles in gene regulation and other cellular processes. This Review ...outlines the emerging understanding of lincRNAs in vertebrate animals, with emphases on how they are being identified and current conclusions and questions regarding their genomics, evolution and mechanisms of action.
The carboxy-terminal domain (CTD) extends from the largest subunit of RNA polymerase II (Pol II) as a long, repetitive and largely unstructured polypeptide chain. Throughout the transcription ...process, the CTD is dynamically modified by post-translational modifications, many of which facilitate or hinder the recruitment of key regulatory factors of Pol II that collectively constitute the 'CTD code'. Recent studies have revealed how the physicochemical properties of the CTD promote phase separation in the presence of other low-complexity domains. Here, we discuss the intricacies of the CTD code and how the newly characterized physicochemical properties of the CTD expand the function of the CTD beyond the code.
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