Open AccessChromatin-enriched RNAs mark active and repressive cis-regulation: An analysis of nuclear RNA-seq
Author(s) -
Xingshu Sun,
Zhezhen Wang,
Johnathon M Hall,
Carlos Perez-Cervantes,
Alexander J. Ruthenburg,
Ivan P. Moskowitz,
Michael Gribskov,
Xinan Yang
Publication year - 2020
Publication title -
plos computational biology/plos computational biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.628
H-Index - 182
eISSN - 1553-7358
pISSN - 1553-734X
DOI - 10.1371/journal.pcbi.1007119
Subject(s) - chromatin , biology , enhancer , rna , gene , genetics , gene expression , regulation of gene expression , computational biology , enhancer rnas , non coding rna , long non coding rna , transcription (linguistics) , linguistics , philosophy
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.