Genome-wide measurement of RNA dissociation from chromatin classifies transcripts by their dynamics and reveals rapid dissociation of enhancer lncRNAs

TY - JOUR

T1 - Genome-wide measurement of RNA dissociation from chromatin classifies transcripts by their dynamics and reveals rapid dissociation of enhancer lncRNAs

AU - Ntini, Evgenia

AU - Budach, Stefan

AU - Vang Ørom, Ulf A.

AU - Marsico, Annalisa

N1 - Publisher Copyright: © 2023 Elsevier Inc.

PY - 2023/10

Y1 - 2023/10

N2 - Long non-coding RNAs (lncRNAs) are involved in gene expression regulation in cis. Although enriched in the cell chromatin fraction, to what degree this defines their regulatory potential remains unclear. Furthermore, the factors underlying lncRNA chromatin tethering, as well as the molecular basis of efficient lncRNA chromatin dissociation and its impact on enhancer activity and target gene expression, remain to be resolved. Here, we developed chrTT-seq, which combines the pulse-chase metabolic labeling of nascent RNA with chromatin fractionation and transient transcriptome sequencing to follow nascent RNA transcripts from their transcription on chromatin to release and allows the quantification of dissociation dynamics. By incorporating genomic, transcriptomic, and epigenetic metrics, as well as RNA-binding protein propensities, in machine learning models, we identify features that define transcript groups of different chromatin dissociation dynamics. Notably, lncRNAs transcribed from enhancers display reduced chromatin retention, suggesting that, in addition to splicing, their chromatin dissociation may shape enhancer activity.

AB - Long non-coding RNAs (lncRNAs) are involved in gene expression regulation in cis. Although enriched in the cell chromatin fraction, to what degree this defines their regulatory potential remains unclear. Furthermore, the factors underlying lncRNA chromatin tethering, as well as the molecular basis of efficient lncRNA chromatin dissociation and its impact on enhancer activity and target gene expression, remain to be resolved. Here, we developed chrTT-seq, which combines the pulse-chase metabolic labeling of nascent RNA with chromatin fractionation and transient transcriptome sequencing to follow nascent RNA transcripts from their transcription on chromatin to release and allows the quantification of dissociation dynamics. By incorporating genomic, transcriptomic, and epigenetic metrics, as well as RNA-binding protein propensities, in machine learning models, we identify features that define transcript groups of different chromatin dissociation dynamics. Notably, lncRNAs transcribed from enhancers display reduced chromatin retention, suggesting that, in addition to splicing, their chromatin dissociation may shape enhancer activity.

KW - chromatin dissociation dynamics

KW - co-transcriptional splicing

KW - enhancer

KW - enhancer-associated lncRNAs

KW - lncRNAs

KW - machine learning

KW - nascent RNA transcription

KW - predictive models

KW - RNA processing

KW - RNA-binding protein interactions

UR - http://www.scopus.com/inward/record.url?scp=85173908042&partnerID=8YFLogxK

U2 - 10.1016/j.cels.2023.09.005

DO - 10.1016/j.cels.2023.09.005

M3 - Journal article

C2 - 37857083

AN - SCOPUS:85173908042

SN - 2405-4712

VL - 14

SP - 906-922.e6

JO - Cell Systems

JF - Cell Systems

IS - 10

ER -