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Epigenomic and RNA structural correlates of polyadenylation.

ABSTRACT: Polyadenylation (poly(A)) of mRNA plays a critical role in regulating gene expression. Identifying the sequence, structural, and epigenomic determinants of poly(A) site usage is an important long term goal. Several cis elements that mediate poly(A) regulation have been identified. Highly used poly(A) sites are also known to have a greater nucleosome occupancy in the immediate downstream. However, a detailed exploration of additional epigenomic and mRNA structural correlates of poly(A) site usage has not been reported. Importantly, functional interaction between sequence, structure, and the epigenome in determining the poly(A) site usage is not known. We show that highly used poly(A) sites are positively associated with an mRNA structure that is energetically more favorable and one that better exposes a critical polyadenylation cis element. In exploring potential interplay between RNA and chromatin structure, we found that a stronger nucleosome occupancy downstream of poly(A) site strongly correlated with (1) a more favorable mRNA structure, and (2) a greater accumulation of RNA Polymerase II (PolII) at the poly(A) site. Further analysis suggested a causal relationship pointing from PolII accumulation to a stable RNA structure. Additionally, we found that distinct patterns of histone modifications characterize poly(A) sites and these epigenetic patterns alone can distinguish true poly(A) sites with ~76% accuracy and also discriminate between high and low usage poly(A) sites with ~74% accuracy. Our results suggest a causative link between chromatin structure and mRNA structure whereby a compacted chromatin downstream of the poly(A) site slows down the elongating transcript, thus facilitating the folding of nascent mRNA in a favorable structure at poly(A) site during transcription. Additionally we report hitherto unknown epigenomic correlates for poly(A) site usage.

SUBMITTER: Khaladkar M

PROVIDER: S-EPMC3218514 | biostudies-literature | 2011 May-Jun

REPOSITORIES: biostudies-literature

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Epigenomic and RNA structural correlates of polyadenylation.

Khaladkar Mugdha M Smyda Mark M Hannenhalli Sridhar S

RNA biology 20110501 3

Polyadenylation (poly(A)) of mRNA plays a critical role in regulating gene expression. Identifying the sequence, structural, and epigenomic determinants of poly(A) site usage is an important long term goal. Several cis elements that mediate poly(A) regulation have been identified. Highly used poly(A) sites are also known to have a greater nucleosome occupancy in the immediate downstream. However, a detailed exploration of additional epigenomic and mRNA structural correlates of poly(A) site usage ...[more]

PMID: 21508683

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Project description:BackgroundOne of the essential processing events during pre-mRNA maturation is the post-transcriptional addition of a polyadenine [poly(A)] tail. The 3'-end poly(A) track protects mRNA from unregulated degradation, and indicates the integrity of mRNA through recognition by mRNA export and translation machinery. The position of a poly(A) site is predetermined by signals in the pre-mRNA sequence that are recognized by a complex of polyadenylation factors. These signals are generally tri-part sequence patterns around the cleavage site that serves as the future poly(A) site. In plants, there is little sequence conservation among these signal elements, which makes it difficult to develop an accurate algorithm to predict the poly(A) site of a given gene. We attempted to solve this problem.ResultsBased on our current working model and the profile of nucleotide sequence distribution of the poly(A) signals and around poly(A) sites in Arabidopsis, we have devised a Generalized Hidden Markov Model based algorithm to predict potential poly(A) sites. The high specificity and sensitivity of the algorithm were demonstrated by testing several datasets, and at the best combinations, both reach 97%. The accuracy of the program, called poly(A) site sleuth or PASS, has been demonstrated by the prediction of many validated poly(A) sites. PASS also predicted the changes of poly(A) site efficiency in poly(A) signal mutants that were constructed and characterized by traditional genetic experiments. The efficacy of PASS was demonstrated by predicting poly(A) sites within long genomic sequences.ConclusionBased on the features of plant poly(A) signals, a computational model was built to effectively predict the poly(A) sites in Arabidopsis genes. The algorithm will be useful in gene annotation because a poly(A) site signifies the end of the transcript. This algorithm can also be used to predict alternative poly(A) sites in known genes, and will be useful in the design of transgenes for crop genetic engineering by predicting and eliminating undesirable poly(A) sites.

Dataset Information

Epigenomic and RNA structural correlates of polyadenylation.

Publications

Epigenomic and RNA structural correlates of polyadenylation.

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