The Interlocking Lives of LARP7: Fine-Tuning Transcription, RNA Modification, and Splicing through Multiple Non-coding RNAs

Frilander, Mikko J.; Barborič, Matjaž

doi:10.1016/j.molcel.2020.03.015

Cited by 6 publications

(7 citation statements)

References 14 publications

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“…4d-e). LC-DICs were positively associated with 1) enhancer markers (H3K27ac, H3K4me1, P300); 2) Pol2 peaks, the Pol2-pausing regulator (LARP7) 29 and a transcriptional repressor (ZBTB1) 30 ; 3) tissue-specific regulators (FOXA1 26 and TF binding, which is consistent with our analysis above, indicative of the TF-independent chromatin de-compaction. Taken together, the application of machine learning successfully isolated special subsets of cohesin sites (DICs) from all cohesin sites, which also provided us with additional characteristics by which they can be identified.…”

Section: Machine Learning Analysis Of Dic Featuressupporting

confidence: 89%

“…4d-e). LC-DICs were positively associated with 1) enhancer markers (H3K27ac, H3K4me1, P300); 2) Pol2 peaks, the Pol2-pausing regulator (LARP7) 29 and a transcriptional repressor (ZBTB1) 30 ; 3) tissue-specific regulators (FOXA1 26 , HSF1 31 , ER 18 ). Both LC-DICs and HC-DICs were positively associated with open chromatin (FAIRE-open, DNase-open) and chromatin de-compaction (ΔDLR), and were negatively associated with H3K27me3 and CpG island levels.…”

Section: Resultsmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted October 1, 2021. ; https://doi.org/10.1101/2021.09. 29.462097 doi: bioRxiv preprint 3 several TFs from MCF-7 cells with or without transcription stimulus. We also used many publicly available datasets including Hi-C, ChIP-seq, RNA-seq and chromatin interaction analysis by paired-end tag (ChIA-PET).…”

Section: Introductionmentioning

confidence: 99%

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Large-scale multi-omics analysis suggests specific roles for intragenic cohesin in transcriptional regulation

Wang

Bando

Shirahige

et al. 2021

Preprint

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Cohesin, an essential protein complex for chromosome segregation, regulates transcription through a variety of mechanisms. It is not a trivial task to genome-widely assign the diverse cohesin functions. Moreover, the context-specific roles of cohesin-mediated interactions, especially on intragenic regions, have not been thoroughly investigated. Here we performed a comprehensive characterization of cohesin binding sites in several human cell types. We integrated epigenomic, transcriptomic and chromatin interaction data with and without transcriptional stimulation, to explore context-specific functions of intragenic cohesin related to gene activation. We identified a new subset of cohesin binding sites, decreased intragenic cohesin sites (DICs), which have a different function from previously known ones. The intron-enriched DICs were negatively correlated with transcriptional regulation: a subgroup of DICs were related to enhancer markers and paused RNA polymerase II, whereas others contributed to chromatin architecture. We implemented machine learning and successfully isolated DICs with distinct genomic features. We observed DICs in various cell types, including cells from cohesinopathy patients. These results suggest a previously unidentified function of cohesin at intragenic regions for transcription regulation.

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Section: Machine Learning Analysis Of Dic Featuressupporting

confidence: 89%

“…4d-e). LC-DICs were positively associated with 1) enhancer markers (H3K27ac, H3K4me1, P300); 2) Pol2 peaks, the Pol2-pausing regulator (LARP7) 29 and a transcriptional repressor (ZBTB1) 30 ; 3) tissue-specific regulators (FOXA1 26 , HSF1 31 , ER 18 ). Both LC-DICs and HC-DICs were positively associated with open chromatin (FAIRE-open, DNase-open) and chromatin de-compaction (ΔDLR), and were negatively associated with H3K27me3 and CpG island levels.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Large-scale multi-omics analysis suggests specific roles for intragenic cohesin in transcriptional regulation

Wang

Bando

Shirahige

et al. 2021

Preprint

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“…Histone level methylation ( carm1 ) alters the structure and availability of DNA for transcription, promoting phenotypic modification at the DNA level, allowing lake sturgeon to rapidly respond to environmental change (Burggren and Crews, 2014). Additionally, post-transcriptional modifications by pre-mRNA splicing ( larp7 ; Frilander and Barboric, 2020) can provide enhanced transcriptional plasticity, with the potential for enhanced adaptation to environmental change (Steward et al, 2022). Together, these two processes enhance the ability of lake sturgeon to modify the production of mRNAs prior to translation, and likely promote phenotypic plasticity towards increasing temperatures.…”

Section: Discussionmentioning

confidence: 99%

Elevated temperatures reduce population-specific transcriptional plasticity in developing lake sturgeon (Acipenser fulvescens)

Bugg

Thorstensen

Marshall

et al. 2022

Preprint

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Rising mean and variance in temperatures elevate threats to endangered freshwater species like the lake sturgeon, Acipenser fulvescens. Previous research has demonstrated that higher temperatures in early development result in physiological consequences for lake sturgeon populations throughout Manitoba, Canada, with alteration of metabolic rate, thermal tolerance, transcriptional responses, growth, and mortality. In the present study, we acclimated lake sturgeon from northern and southern populations within Manitoba to current and future projected environmental temperatures of 16, 20, and 24C for 30 days, and measured gill transcriptional responses using RNAseq. We found population-specific and acclimation-specific responses to the thermal treatments, as well as conserved molecular responses between northern and southern sturgeon populations. Expression profiles revealed a gradient in transcriptional responses consistent with acclimation temperature, with a higher number of differentially expressed transcripts observed in the southern compared to the northern lake sturgeon population as temperatures increase, indicating enhanced transcriptional plasticity. Overall lake sturgeon populations responded to thermal acclimation by upregulating the expression of transcripts involved in transcriptional and translational regulation, mitochondrial function, pathogen responses, and DNA damage, as well as genes associated with pre- and post-transcriptional processes (i.e., methylation, alternative splicing). Further, both populations upregulated transcript expression related to cell structural damage as temperatures increased to 20C, but the northern population also responded with increases in damage signaling and recruitment of mitochondrial processes involved in ATP production. Ultimately, these transcriptional responses highlight molecular consequences of increasing temperatures for divergent lake sturgeon populations during vulnerable early developmental periods and the critical influence of transcriptome plasticity on acclimation capacity.

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“…Their presence can optimize the interactions of snRNAs with each other and with pre-mRNAs, as well as affect the binding of spliceosomal proteins. It was recently reported that LARP7, which is a component of the P-TEFb complex, facilitates the assembly of small nucleolar RNA (snoRNA) with U6 snRNA, promoting efficient Nm deposition [123][124][125]. The lack of LARP7 prevents U6 methylation and leads to several splicing defects.…”

Section: Trends Trends In In Genetics Geneticsmentioning

confidence: 99%

Anything but Ordinary – Emerging Splicing Mechanisms in Eukaryotic Gene Regulation

Gehring

Roignant

2021

Trends in Genetics

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Splicing of precursor mRNAs (pre-mRNA) is an important step during eukaryotic gene expression. The identification of the actual splice sites and the proper removal of introns are essential for the production of the desired mRNA isoforms and their encoded proteins. While the basic mechanisms of splicing regulation are well understood, recent work has uncovered a growing number of noncanonical splicing mechanisms that play key roles in the regulation of gene expression. In this review, we summarize the current principles of splicing regulation, including the impact of cis and trans regulatory elements, as well as the influence of chromatin structure, transcription, and RNA modifications. We further discuss the recent development of emerging splicing mechanisms, such as recursive and back splicing, and their impact on gene expression. Significance of Splicing for Gene ExpressionThe genomes of all eukaryotes contain introns, but their number, size, and distribution vary considerably between different species [1]. In humans, for example, the average gene contains about eight introns, whereas genes in Drosophila melanogaster have fewer introns, which on average are also shorter (5.8 kb versus 1.5 kb) [1-3]. The correct identification and removal of introns by the splicing machinery is a central, conserved step during gene expression in all eukaryotes, and mutations that alter the sequence of splice sites or elicit splicing errors are often associated with disease [4,5]. Furthermore, the noncontinuous exon-intron structure of eukaryotic genes allows the formation of alternative mRNA isoforms. During this process the exons of a pre-mRNA are assembled in different ways; for example, by skipping one or several exons or using alternative splice sites [6]. Alternative splice variants of one gene may encode different protein isoforms, which in extreme cases can have opposite functions [7]. The occurrence of alternative splicing provides exciting new possibilities for gene regulation and is responsible for the remarkable transcriptome and proteome diversity in metazoans [8,9]. Of all human genes, only 5% consist of a single exon [10] and >90% are alternatively spliced [11][12][13]. Alternative splicing is regulated by interactions of RNA-binding proteins (RBPs; see Glossary) and splicing factors with sequences in the pre-mRNA, and by base-pairing between complementary RNA sequences in cis and in trans [6,14]. Since most splicing decisions occur concomitantly to transcription, the interaction of RBPs with pre-mRNAs can be impacted by chromatin structure, transcription factors as well as RNA modifications. In this review, we first summarize the general mechanisms of splicing regulation that integrate all these parameters, and in the second part, we discuss the emergence of new splicing mechanisms, also referred to as noncanonical splicing. General Principles of Splicing RegulationRegulation by the Spliceosome and Other RBPs Pre-mRNA splicing in eukaryotes is carried out by the spliceosome [15][16][17]. This large RNA-protein com...

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The Interlocking Lives of LARP7: Fine-Tuning Transcription, RNA Modification, and Splicing through Multiple Non-coding RNAs

Abstract: Elegant studies by Hasler et al. (2020) and Wang et al. (2020) uncover a novel role of LARP7 in facilitating the 2 0 -O-methylation of the spliceosomal U6 snRNA, which is functionally required for fidelity of pre-mRNA splicing and development of male germ cells.

Cited by 6 publications

References 14 publications

Large-scale multi-omics analysis suggests specific roles for intragenic cohesin in transcriptional regulation

Large-scale multi-omics analysis suggests specific roles for intragenic cohesin in transcriptional regulation

Elevated temperatures reduce population-specific transcriptional plasticity in developing lake sturgeon (Acipenser fulvescens)

Anything but Ordinary – Emerging Splicing Mechanisms in Eukaryotic Gene Regulation

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