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Principles for RNA metabolism and alternative transcription initiation within closely spaced promoters

ABSTRACT: Mammalian transcriptomes are complex and formed by extensive promoter activity. Moreover, gene promoters are largely divergent and initiate transcription of reverse-oriented promoter upstream transcripts (PROMPTs). Although PROMPTs are commonly terminated early, influenced by early polyadenylation (pA) sites, promoters often cluster so that the divergent activity of one might impact another. Here, we find that the distance between promoters strongly correlates with the expression, stability and length of their associated PROMPTs. Adjacent promoters driving divergent mRNA transcription support PROMPT formation, but due to pA site constraints, these transcripts tend to spread into the neighboring mRNA on the same strand. This mechanism to derive new alternative mRNA transcription start sites (TSSs) is also evident at closely spaced promoters supporting convergent mRNA transcription. We suggest that basic building blocks of divergently transcribed core promoter pairs, in combination with the wealth of TSSs in mammalian genomes, provides a framework with which evolution shapes transcriptomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE75183 | GEO | 2016/05/13

SECONDARY ACCESSION(S): PRJNA302735

REPOSITORIES: GEO

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Principles for RNA metabolism and alternative transcription initiation within closely spaced promoters

Project description:Mammalian transcriptomes are complex and formed by extensive promoter activity. Moreover, gene promoters are largely divergent and initiate transcription of reverse-oriented promoter upstream transcripts (PROMPTs). Although PROMPTs are commonly terminated early, influenced by early polyadenylation (pA) sites, promoters often cluster so that the divergent activity of one might impact another. Here, we find that the distance between promoters strongly correlates with the expression, stability and length of their associated PROMPTs. Adjacent promoters driving divergent mRNA transcription support PROMPT formation, but due to pA site constraints, these transcripts tend to spread into the neighboring mRNA on the same strand. This mechanism to derive new alternative mRNA transcription start sites (TSSs) is also evident at closely spaced promoters supporting convergent mRNA transcription. We suggest that basic building blocks of divergently transcribed core promoter pairs, in combination with the wealth of TSSs in mammalian genomes, provides a framework with which evolution shapes transcriptomes. Mapping of paired 5â?? and 3â??ends of capped and polyadenylated RNAs from RRP40-depleted and eGFP control HeLa cells and using transcript isoform sequencing (TIF-Seq, see Pelechano et al. Nat Protoc 2014 (PMID: 24967623) and Pelechano et al. Nature 2013 (PMID: 23615609)).

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Analysis of transcription start sites from nascent RNA identifies a unified architecture of initiation at mammalian promoters and enhancers (GRO-seq)

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Analysis of transcription start sites from nascent RNA identifies a unified architecture of initiation at mammalian promoters and enhancers (GRO-cap)

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High-throughput functional analysis of lncRNA core promoters elucidates rules governing tissue specificity

Project description:Bidirectional transcription initiates at both coding and non-coding genomic elements, including mRNA and long non-coding RNA (lncRNA) promoters and enhancer RNAs (eRNAs). However, each class has different tissue-specific expression profiles with lncRNAs and eRNAs being the most tissue-specific. How these complex differences in expression profiles and tissue-specificities are encoded in a single DNA sequence, however, remains an open question. Here, we address this question using multiple computational and experimental approaches, including massively parallel reporter assays (MPRA). As most transcription factors (TFs) are enriched near the transcription start sites (TSSs) of both promoters and enhancers, we focus our analyses on these core promoter regions. We find that divergent lncRNA and mRNA core promoters have higher capacities to drive transcription than non-divergent lncRNA and mRNA core promoters, respectively. Conversely, lincRNAs and eRNAs are more tissue-specific than divergent genes. This higher tissue-specificity is strongly associated with having less complex TF motif profiles at the core promoter. We confirm these findings using single-nucleotide deletions in MPRA and we identify specific TFs regulating a set of disease-related lncRNAs. Finally, we assess the effects of genetic variation at core promoters and find that 22% of common single nucleotide polymorphisms show significant regulatory effects. Collectively, our findings characterize the important role of core promoter sequences in determining expression levels across both coding and non-coding gene classes and highlight an unexpected role of TF motif architecture in explaining the more restricted expression patterns of lncRNAs and eRNAs.

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The SPARC complex defines RNAPII promoters in Trypanosoma brucei

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Structure of transcription preinitiation complex engaged with the +1 nucleosome

Project description:The preinitiation complex (PIC) assembles on promoters of protein-coding genes to position RNA polymerase II (Pol II) for transcription initiation. Previous structural studies revealed the PIC on different promoters, but did not address how the PIC assembles in chromatin. In the yeast Saccharomyces cerevisiae, PIC assembly occurs adjacent to the +1 nucleosome that is positioned downstream of the core promoter. Here we present the cryo-EM structure of the yeast PIC bound to promoter DNA and the +1 nucleosome at a resolution of 3.4–3.9 Å. The general transcription factor TFIIH forms four contacts with the nucleosome, indicating how PIC assembly can be assisted by the +1 nucleosome. The TFIIH subunit Ssl2 (XPB in human TFIIH) forms a wedge between promoter DNA and the nucleosome, stabilizing two turns of DNA that are detached from the nucleosome. During subsequent scanning for the transcription start site (TSS), three additional turns of DNA can be detached before the partially unraveled nucleosome may counteract further scanning, explaining why TSSs are located at a distance of ~60 bp from the dyad of the +1 nucleosome in yeast.

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2023-05-04 | GSE221252 | GEO

Histone acetyltransferase 2 links H4 acetylation, H2A.Z deposition and transcription start site-choice in African trypanosomes

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RSC mediated nucleosome positioning and GRFs form barriers in promoters to limit divergent noncoding transcription [nascent RNA-Seq]

Project description:The directionality of gene promoters, the proportion of protein coding over divergent noncoding transcription, is highly variable and regulated. How promoter directionality is controlled remains poorly understood. We show that chromatin remodelling complex RSC, general regulatory factors (GRFs) including transcription factors (TFs) can facilitate promoter directionality by attenuating divergent noncoding transcription. Depletion of RSC increased divergent noncoding and decreased protein coding transcription of promoters with strong directionality. Consistent with RSC’s role in regulating chromatin, RSC depletion negatively impacts nucleosome positions upstream of the nucleosome depleted region where divergent transcription initiates, suggesting that nucleosome positioning upstream in promoters physically blocks the recruitment of transcription machinery. Likewise, divergent transcription can be suppressed by targeting GRFs and TFs or the bulky dCas9 protein to transcriptional initiation sites. We propose that RSC mediated nucleosome positioning, GRFs including TFs form the physical barriers in promoters for limiting of divergent transcription, thereby controlling promoter directionality.

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