Publication Date:
2013-06-25
Description:
Transcription of the mammalian genome is pervasive, but productive transcription outside of protein-coding genes is limited by unknown mechanisms. In particular, although RNA polymerase II (RNAPII) initiates divergently from most active gene promoters, productive elongation occurs primarily in the sense-coding direction. Here we show in mouse embryonic stem cells that asymmetric sequence determinants flanking gene transcription start sites control promoter directionality by regulating promoter-proximal cleavage and polyadenylation. We find that upstream antisense RNAs are cleaved and polyadenylated at poly(A) sites (PASs) shortly after initiation. De novo motif analysis shows PAS signals and U1 small nuclear ribonucleoprotein (snRNP) recognition sites to be the most depleted and enriched sequences, respectively, in the sense direction relative to the upstream antisense direction. These U1 snRNP sites and PAS sites are progressively gained and lost, respectively, at the 5' end of coding genes during vertebrate evolution. Functional disruption of U1 snRNP activity results in a dramatic increase in promoter-proximal cleavage events in the sense direction with slight increases in the antisense direction. These data suggest that a U1-PAS axis characterized by low U1 snRNP recognition and a high density of PASs in the upstream antisense region reinforces promoter directionality by promoting early termination in upstream antisense regions, whereas proximal sense PAS signals are suppressed by U1 snRNP. We propose that the U1-PAS axis limits pervasive transcription throughout the genome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720719/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720719/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Almada, Albert E -- Wu, Xuebing -- Kriz, Andrea J -- Burge, Christopher B -- Sharp, Phillip A -- GM-085319/GM/NIGMS NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R01 CA133404/CA/NCI NIH HHS/ -- R01 GM034277/GM/NIGMS NIH HHS/ -- R01 HG002439/HG/NHGRI NIH HHS/ -- R01-CA133404/CA/NCI NIH HHS/ -- R01-GM34277/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jul 18;499(7458):360-3. doi: 10.1038/nature12349. Epub 2013 Jun 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23792564" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cells, Cultured
;
Evolution, Molecular
;
Mice
;
*Polyadenylation
;
*Promoter Regions, Genetic
;
RNA Cleavage
;
RNA, Antisense/metabolism
;
Ribonucleoprotein, U1 Small Nuclear/*metabolism
;
*Transcription Elongation, Genetic
;
Transcription Termination, Genetic
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
