PMID- 28410363
OWN - NLM
STAT- MEDLINE
DCOM- 20170627
LR  - 20181113
IS  - 1553-7358 (Electronic)
IS  - 1553-734X (Print)
IS  - 1553-734X (Linking)
VI  - 13
IP  - 4
DP  - 2017 Apr
TI  - Highly accessible AU-rich regions in 3' untranslated regions are hotspots for 
      binding of regulatory factors.
PG  - e1005460
LID - 10.1371/journal.pcbi.1005460 [doi]
LID - e1005460
AB  - Post-transcriptional regulation is regarded as one of the major processes 
      involved in the regulation of gene expression. It is mainly performed by RNA 
      binding proteins and microRNAs, which target RNAs and typically affect their 
      stability. Recent efforts from the scientific community have aimed at 
      understanding post-transcriptional regulation at a global scale by using 
      high-throughput sequencing techniques such as cross-linking and 
      immunoprecipitation (CLIP), which facilitates identification of binding sites of 
      these regulatory factors. However, the diversity in the experimental procedures 
      and bioinformatics analyses has hindered the integration of multiple datasets and 
      thus limited the development of an integrated view of post-transcriptional 
      regulation. In this work, we have performed a comprehensive analysis of 107 CLIP 
      datasets from 49 different RBPs in HEK293 cells to shed light on the complex 
      interactions that govern post-transcriptional regulation. By developing a more 
      stringent CLIP analysis pipeline we have discovered the existence of conserved 
      regulatory AU-rich regions in the 3'UTRs where miRNAs and RBPs that regulate 
      several processes such as polyadenylation or mRNA stability bind. Analogous to 
      promoters, many factors have binding sites overlapping or in close proximity in 
      these hotspots and hence the regulation of the mRNA may depend on their relative 
      concentrations. This hypothesis is supported by RBP knockdown experiments that 
      alter the relative concentration of RBPs in the cell. Upon AGO2 knockdown (KD), 
      transcripts containing "free" target sites show increased expression levels 
      compared to those containing target sites in hotspots, which suggests that target 
      sites within hotspots are less available for miRNAs to bind. Interestingly, these 
      hotspots appear enriched in genes with regulatory functions such as DNA binding 
      and RNA binding. Taken together, our results suggest that hotspots are functional 
      regulatory elements that define an extra layer of regulation of 
      post-transcriptional regulatory networks.
FAU - Plass, Mireya
AU  - Plass M
AUID- ORCID: 0000-0002-9891-2723
AD  - Section for Computational and RNA Biology, Department of Biology, University of 
      Copenhagen, Ole Maaloes Vej 5, Copenhagen, Denmark.
FAU - Rasmussen, Simon H
AU  - Rasmussen SH
AD  - Section for Computational and RNA Biology, Department of Biology, University of 
      Copenhagen, Ole Maaloes Vej 5, Copenhagen, Denmark.
FAU - Krogh, Anders
AU  - Krogh A
AUID- ORCID: 0000-0002-5147-6282
AD  - Section for Computational and RNA Biology, Department of Biology, University of 
      Copenhagen, Ole Maaloes Vej 5, Copenhagen, Denmark.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170414
PL  - United States
TA  - PLoS Comput Biol
JT  - PLoS computational biology
JID - 101238922
RN  - 0 (3' Untranslated Regions)
RN  - 0 (MicroRNAs)
RN  - 0 (RNA-Binding Proteins)
SB  - IM
MH  - 3' Untranslated Regions/*genetics
MH  - Binding Sites/*genetics
MH  - Computational Biology
MH  - HEK293 Cells
MH  - Humans
MH  - Immunoprecipitation
MH  - MicroRNAs/*genetics/metabolism
MH  - Polyadenylation/genetics
MH  - RNA-Binding Proteins/*genetics/metabolism
PMC - PMC5409497
COIS- The authors have declared that no competing interests exist.
EDAT- 2017/04/15 06:00
MHDA- 2017/06/28 06:00
PMCR- 2017/04/01
CRDT- 2017/04/15 06:00
PHST- 2016/04/25 00:00 [received]
PHST- 2017/03/14 00:00 [accepted]
PHST- 2017/04/28 00:00 [revised]
PHST- 2017/04/15 06:00 [pubmed]
PHST- 2017/06/28 06:00 [medline]
PHST- 2017/04/15 06:00 [entrez]
PHST- 2017/04/01 00:00 [pmc-release]
AID - PCOMPBIOL-D-16-00675 [pii]
AID - 10.1371/journal.pcbi.1005460 [doi]
PST - epublish
SO  - PLoS Comput Biol. 2017 Apr 14;13(4):e1005460. doi: 10.1371/journal.pcbi.1005460. 
      eCollection 2017 Apr.