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- Title
Chromatin-enriched RNAs mark active and repressive cis-regulation: An analysis of nuclear RNA-seq.
- Authors
Sun, Xiangying; Wang, Zhezhen; Hall, Johnathon M.; Perez-Cervantes, Carlos; Ruthenburg, Alexander J.; Moskowitz, Ivan P.; Gribskov, Michael; Yang, Xinan H.
- Abstract
Long noncoding RNAs (lncRNAs) localize in the cell nucleus and influence gene expression through a variety of molecular mechanisms. Chromatin-enriched RNAs (cheRNAs) are a unique class of lncRNAs that are tightly bound to chromatin and putatively function to locally cis-activate gene transcription. CheRNAs can be identified by biochemical fractionation of nuclear RNA followed by RNA sequencing, but until now, a rigorous analytic pipeline for nuclear RNA-seq has been lacking. In this study, we survey four computational strategies for nuclear RNA-seq data analysis and develop a new pipeline, Tuxedo-ch, which outperforms other approaches. Tuxedo-ch assembles a more complete transcriptome and identifies cheRNA with higher accuracy than other approaches. We used Tuxedo-ch to analyze benchmark datasets of K562 cells and further characterize the genomic features of intergenic cheRNA (icheRNA) and their similarity to enhancer RNAs (eRNAs). We quantify the transcriptional correlation of icheRNA and adjacent genes and show that icheRNA is more positively associated with neighboring gene expression than eRNA or cap analysis of gene expression (CAGE) signals. We also explore two novel genomic associations of cheRNA, which indicate that cheRNAs may function to promote or repress gene expression in a context-dependent manner. IcheRNA loci with significant levels of H3K9me3 modifications are associated with active enhancers, consistent with the hypothesis that enhancers are derived from ancient mobile elements. In contrast, antisense cheRNA (as-cheRNA) may play a role in local gene repression, possibly through local RNA:DNA:DNA triple-helix formation. Author summary: Nuclear RNA-seq provides a powerful way to profile the transcriptional landscape, especially the noncoding transcriptome. Through analyzing nuclear RNA-seq, the chromatin-enriched RNA (cheRNA) class of gene regulatory non-coding RNAs was identified. The computational framework presented here provides a reliable approach to identifying cheRNAs from nuclear RNA-seq, and for studying cell-type specific gene regulation. We find that intergenic cheRNA, including transcripts mapped to regions with high levels of classically repressive H3K9me3-marks, may act as a transcriptional activator. In contrast, antisense cheRNA, which originates from the DNA strand complementary to the candidate target protein-coding gene may interact with diverse chromatin modulators to repress local transcription. Our new pipeline allows the identification of a more complete set of cheRNAs than other approaches. A future challenge will be to refine the functional mechanisms of cheRNAs by exploring their regulatory roles, which are involved in diverse molecular and cellular processes in humans and other organisms.
- Subjects
NUCLEOTIDE sequence; RNA; GENETIC regulation; REGULATOR genes; NON-coding RNA; LINCRNA
- Publication
PLoS Computational Biology, 2020, Vol 16, Issue 2, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1007119