Transposable elements (TEs) are repetitive DNA sequences with the ability to replicate across genomes and generate mutations with major transcriptional effects. Epigenetic silencing mechanisms that target TEs to limit th...Transposable elements (TEs) are repetitive DNA sequences with the ability to replicate across genomes and generate mutations with major transcriptional effects. Epigenetic silencing mechanisms that target TEs to limit their activity, including DNA methylation, add to the range of gene expression variants generated by TEs. Here, using the iconic gene flowering locus C ( as a case study I discuss the multiple ways by which TEs can affect the expression of genes and contribute to the adaptation of plants to changing environments.
Plants have a high level of developmental plasticity that allows them to respond and adapt to changes in the environment. Among the environmental cues, light controls almost every aspect of life cycle, including seed ma...Plants have a high level of developmental plasticity that allows them to respond and adapt to changes in the environment. Among the environmental cues, light controls almost every aspect of life cycle, including seed maturation, seed germination, seedling de-etiolation and flowering time. Light signals induce massive reprogramming of gene expression, producing changes in RNA polymerase II transcription, alternative splicing, and chromatin state. Since splicing reactions occur mainly while transcription takes place, the regulation of RNAPII transcription has repercussions in the splicing outcomes. This cotranscriptional nature allows a functional coupling between transcription and splicing, in which properties of the splicing reactions are affected by the transcriptional process. Chromatin landscapes influence both transcription and splicing. In this review, we highlight, summarize and discuss recent progress in the field to gain a comprehensive insight on the cross-regulation between chromatin state, RNAPII transcription and splicing decisions in plants, with a special focus on light-triggered responses. We also introduce several examples of transcription and splicing factors that could be acting as coupling factors in plants. Unravelling how these connected regulatory networks operate, can help in the design of better crops with higher productivity and tolerance.
Boots JL, von Pelchrzim F, Weiss A
… +8 more, Zimmermann B, Friesacher T, Radtke M, Żywicki M, Chen D, Matylla-Kulińska K, Zagrovic B, Schroeder R
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· 2020 Oct · PMID 32663063
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Transcription elongation is a highly regulated process affected by many proteins, RNAs and the underlying DNA. Here we show that the nascent RNA can interfere with transcription in human cells, extending our previous fin...Transcription elongation is a highly regulated process affected by many proteins, RNAs and the underlying DNA. Here we show that the nascent RNA can interfere with transcription in human cells, extending our previous findings from bacteria and yeast. We identified a variety of Pol II-binding aptamers (RAPs), prominent in repeat elements such as ACRO1 satellites, LINE1 retrotransposons and CA simple repeats, and also in several protein-coding genes. ACRO1 repeat, when translated , exhibits ~50% identity with the Pol II CTD sequence. Taken together with a recent proposal that proteins in general tend to interact with RNAs similar to their cognate mRNAs, this suggests a mechanism for RAP binding. Using a reporter construct, we show that ACRO1 potently inhibits Pol II elongation . We propose a novel mode of transcriptional regulation in humans, in which the nascent RNA binds Pol II to silence its own expression.
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· 2020 Apr · PMID 32522085
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UNLABELLED: The majority of eukaryotic messenger RNA precursors (pre-mRNAs) undergo cleavage and polyadenylation at their 3' end. This canonical 3'-end processing depends on sequence elements in the pre-mRNA as well as a...UNLABELLED: The majority of eukaryotic messenger RNA precursors (pre-mRNAs) undergo cleavage and polyadenylation at their 3' end. This canonical 3'-end processing depends on sequence elements in the pre-mRNA as well as a mega-dalton protein machinery. The cleavage site in mammalian pre-mRNAs is located between an upstream poly(A) signal, most frequently an AAUAAA hexamer, and a GU-rich downstream sequence element. This review will summarize recent advances from the studies on this canonical 3'-end processing machinery. They have revealed the molecular mechanism for the recognition of the poly(A) signal and provided the first glimpse into the overall architecture of the machinery. The studies also show that the machinery is highly dynamic conformationally, and extensive re-arrangements are necessary for its activation. Inhibitors targeting the active site of the CPSF73 nuclease of this machinery have anti-cancer, anti-inflammatory and anti-protozoal effects, indicating that CPSF73 and pre-mRNA 3'-end processing in general are attractive targets for drug discovery. ABBREVIATIONS:APA: alternative polyadenylation; β-CASP: metallo-β-lactamase-associated CPSF Artemis SNM1/PSO2; CTD: C-terminal domain; CF: cleavage factor; CPF: cleavage and polyadenylation factor; CPSF: cleavage and polyadenylation specificity factor; CstF: cleavage stimulation factor; DSE: downstream element; HAT: half a TPR; HCC: histone pre-mRNA cleavage complex; mCF: mammalian cleavage factor; mPSF: mammalian polyadenylation specificity factor; mRNA: messenger RNA; nt: nucleotide; NTD: N-terminal domain; PAP: polyadenylate polymerase; PAS: polyadenylation signal; PIM: mPSF interaction motif; Poly(A): polyadenylation, polyadenylate; Pol II: RNA polymerase II; pre-mRNA: messenger RNA precursor; RRM: RNA recognition module, RNA recognition motif; snRNP: small nuclear ribonucleoprotein; TPR: tetratricopeptide repeat; UTR: untranslated region; ZF: zinc finger.
The advent of novel high-throughput sequencing techniques has revealed that eukaryotic genomes are massively transcribed although only a small fraction of RNAs exhibits protein-coding capacity. In the last years, long no...The advent of novel high-throughput sequencing techniques has revealed that eukaryotic genomes are massively transcribed although only a small fraction of RNAs exhibits protein-coding capacity. In the last years, long noncoding RNAs (lncRNAs) have emerged as regulators of eukaryotic gene expression in a wide range of molecular mechanisms. Plant lncRNAs can be transcribed by alternative RNA polymerases, acting directly as long transcripts or can be processed into active small RNAs. Several lncRNAs have been recently shown to interact with chromatin, DNA or nuclear proteins to condition the epigenetic environment of target genes or modulate the activity of transcriptional complexes. In this review, we will summarize the recent discoveries about the actions of plant lncRNAs in the regulation of gene expression at the transcriptional level.
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· 2020 Apr · PMID 32401151
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The production of mRNA is a dynamic process that is highly regulated by reversible post-translational modifications of the C-terminal domain (CTD) of RNA polymerase II. The CTD is a highly repetitive domain consisting mo...The production of mRNA is a dynamic process that is highly regulated by reversible post-translational modifications of the C-terminal domain (CTD) of RNA polymerase II. The CTD is a highly repetitive domain consisting mostly of the consensus heptad sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. Phosphorylation of serine residues within this repeat sequence is well studied, but modifications of all residues have been described. Here, we focus on integrating newly identified and lesser-studied CTD post-translational modifications into the existing framework. We also review the growing body of work demonstrating crosstalk between different CTD modifications and the functional consequences of such crosstalk on the dynamics of transcriptional regulation.
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· 2020 Feb · PMID 31944157
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Enhancers are cis-acting elements with many sites bound by transcription factors and activate transcription over long distance. Histone modifications are critical for enhancer activity and utilized as hallmarks for the i...Enhancers are cis-acting elements with many sites bound by transcription factors and activate transcription over long distance. Histone modifications are critical for enhancer activity and utilized as hallmarks for the identification of putative enhancers. Monomethylation of histone H3 lysine 4 (H3K4me1) is the mark for enhancer priming; acetylation of histone H3 lysine 27 (H3K27ac) for active enhancers and trimethylation of histone H3 lysine 27 (H3K27me3) for silent enhancers. Recent studies from multiple groups have provided evidence that enhancer reprogramming, especially gain of enhancer activity, is closely related to tumorigenesis and cancer development. In this review, we will summarize the recent discoveries about enhancer regulation and the mechanisms of enhancer reprogramming in tumorigenesis, and discuss the potential application of enhancer manipulation in precision medicine.
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· 2020 Apr · PMID 31880185
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Recent biophysical studies of mycobacterial transcription have shed new light on this fundamental process in a group of bacteria that includes deadly pathogens such as ( ( (), as well as the nonpathogenic (). Most of t...Recent biophysical studies of mycobacterial transcription have shed new light on this fundamental process in a group of bacteria that includes deadly pathogens such as ( ( (), as well as the nonpathogenic (). Most of the research has focused on , the causative agent of tuberculosis (TB), which remains one of the top ten causes of death globally. The enzyme RNA polymerase (RNAP) is responsible for all bacterial transcription and is a target for one of the crucial antibiotics used for TB treatment, rifampicin (Rif). Here, we summarize recent biophysical studies of mycobacterial RNAP that have advanced our understanding of the basic process of transcription, have revealed novel paradigms for regulation, and thus have provided critical information required for developing new antibiotics against this deadly disease.
Cardiello JF, Sanchez GJ, Allen MA
… +1 more, Dowell RD
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· 2020 Feb · PMID 31856658
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Nascent transcription assays, such as global run-on sequencing (GRO-seq) and precision run-on sequencing (PRO-seq), have uncovered a myriad of unstable RNAs being actively produced from numerous sites genome-wide. These...Nascent transcription assays, such as global run-on sequencing (GRO-seq) and precision run-on sequencing (PRO-seq), have uncovered a myriad of unstable RNAs being actively produced from numerous sites genome-wide. These transcripts provide a more complete and immediate picture of the impact of regulatory events. Transcription factors recruit RNA polymerase II, effectively initiating the process of transcription; repressors inhibit polymerase recruitment. Efficiency of recruitment is dictated by sequence elements in and around the RNA polymerase loading zone. A combination of sequence elements and RNA binding proteins subsequently influence the ultimate stability of the resulting transcript. Some of these transcripts are capable of providing feedback on the process, influencing subsequent transcription. By monitoring RNA polymerase activity, nascent assays provide insights into every step of the regulated process of transcription.
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· 2020 Feb · PMID 31829768
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Enhancers are defined as regulatory elements that control transcription in a cell-type and developmental stage-specific manner. They achieve this by physically interacting with their cognate gene promoters. Significantly...Enhancers are defined as regulatory elements that control transcription in a cell-type and developmental stage-specific manner. They achieve this by physically interacting with their cognate gene promoters. Significantly, these interactions can occur through long genomic distances since enhancers may not be near their cognate promoters. The optimal coordination of enhancer-regulated transcription is essential for the function and identity of the cell. Although great efforts to fully understand the principles of this type of regulation are ongoing, other potential functions of the long-range chromatin interactions (LRCIs) involving enhancers are largely unexplored. We recently uncovered a new role for enhancer elements in determining the three-dimensional (3D) structure of the immunoglobulin kappa (Igκ) light chain receptor locus suggesting a structural function for these DNA elements. This enhancer-mediated locus configuration shapes the resulting Igκ repertoire. We also propose a role for enhancers as critical components of sub-topologically associating domain (subTAD) formation and nuclear spatial localization.
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· 2020 Feb · PMID 31823686
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Since the discovery that enhancers can support transcription, the roles of enhancer RNAs have remained largely elusive. We identified that enhancer RNAs interact with and augment bromodomain engagement with acetylated ch...Since the discovery that enhancers can support transcription, the roles of enhancer RNAs have remained largely elusive. We identified that enhancer RNAs interact with and augment bromodomain engagement with acetylated chromatin. Here, we discuss our recent findings and the potential mechanisms underlying the regulation and functions of enhancer RNA-bromodomain associations.
FACT (FAcilitates Chromatin Transactions) is a highly conserved histone chaperone complex in eukaryotic cells that can interact and manipulate nucleosomes in order to promote a variety of DNA-based processes and to maint...FACT (FAcilitates Chromatin Transactions) is a highly conserved histone chaperone complex in eukaryotic cells that can interact and manipulate nucleosomes in order to promote a variety of DNA-based processes and to maintain the integrity of chromatin throughout the genome. Whereas key features of the physical interactions that occur between FACT and nucleosomes have been elucidated in recent years, less is known regarding FACT functional dynamics . Using the system, we now provide evidence that at least at some genes dissociation of the FACT subunit Spt16 from their 3' ends is partially dependent on RNA Polymerase II (Pol II) termination. Combined with other studies, our results are consistent with a two-phase mechanism for FACT dissociation from genes, one that occurs upstream from Pol II dissociation and is Pol II termination-independent and the other that occurs further downstream and is dependent on Pol II termination.
The regulation of gene expression is a fundamental cellular process and its misregulation is a key component of disease. Enhancers are one of the most salient regulatory elements in the genome and help orchestrate proper...The regulation of gene expression is a fundamental cellular process and its misregulation is a key component of disease. Enhancers are one of the most salient regulatory elements in the genome and help orchestrate proper spatiotemporal gene expression during development, in homeostasis, and in response to signaling. Notably, molecular aberrations at enhancers, such as translocations and single nucleotide polymorphisms, are emerging as an important source of human variation and susceptibility to disease. Herein we discuss emerging paradigms addressing how genes are regulated by enhancers, common features of active enhancers, and how non-coding enhancer RNAs (eRNAs) can direct gene expression programs that underlie cellular phenotypes. We survey the current evidence, which suggests that eRNAs can bind to transcription factors, mediate enhancer-promoter interactions, influence RNA Pol II elongation, and act as decoys for repressive cofactors. Furthermore, we discuss current methodologies for the identification of eRNAs and novel approaches to elucidate their functions.
Inorganic phosphate (P), a ubiquitous metabolite, is involved in all major biochemical pathways. We demonstrate that, , MgHPO (the intracellular P form) at physiological concentrations can exist in a metastable supersatu...Inorganic phosphate (P), a ubiquitous metabolite, is involved in all major biochemical pathways. We demonstrate that, , MgHPO (the intracellular P form) at physiological concentrations can exist in a metastable supersaturated dissolved state or as a precipitate. We have shown that in solution, MgHPO strongly stimulates exonuclease nascent transcript cleavage by RNA polymerase. We report here that MgHPO precipitate selectively and efficiently inhibits transcription initiation . In view of the MgHPO solubility and sensitivity of RNA synthesis to MgHPO precipitate, at physiological concentrations, MgHPO should cause a 50-98% inhibition of cellular RNA synthesis, thus exerting a strong regulatory action. The effects of P on transcription will, therefore, reflect the physical state of intracellular P.
Bacteriophages employ small proteins to usurp host molecular machinery, thereby interfering with central metabolic processes in infected bacteria. Generally, phages inhibit or redirect host transcription to favor transcr...Bacteriophages employ small proteins to usurp host molecular machinery, thereby interfering with central metabolic processes in infected bacteria. Generally, phages inhibit or redirect host transcription to favor transcription of their own genomes. Mechanistic and structural studies of phage-modulated host transcription may provide inspirations for the development of novel antibacterial substances.
Circadian clocks regulate the rhythmic expression of thousands of genes underlying the daily oscillations of biological functions. Here, we discuss recent findings showing that circadian clock rhythmic transcriptional ou...Circadian clocks regulate the rhythmic expression of thousands of genes underlying the daily oscillations of biological functions. Here, we discuss recent findings showing that circadian clock rhythmic transcriptional outputs rely on additional mechanisms than just clock gene DNA binding, which may ultimately contribute to the plasticity of circadian transcriptional programs.
Gene expression involves multiple co- and post-transcriptional processes that have been increasingly found intertwined. A recent work by our groups (Chen et al. , 2019) indicates that expression of alternative polyadenyl...Gene expression involves multiple co- and post-transcriptional processes that have been increasingly found intertwined. A recent work by our groups (Chen et al. , 2019) indicates that expression of alternative polyadenylation isoforms in mammalian cells can be controlled by nuclear export activities. This regulation has distinct impacts on genes having different sizes and nucleotide contents, and involves RNA polymerase II distribution toward the 3' end of genes. This work raises a number of intriguing questions concerning how 3' end processing and nuclear export are integrated and how their regulation feeds back to transcription.