Upstream mononucleotide A-repeats play a cis-regulatory role in mammals through the DICER1 and Ago proteins.
A-repeats are the simplest form of tandem repeats and are found ubiquitously throughout genomes. These mononucleotide repeats have been widely believed to be non-functional 'junk' DNA. However, studies in yeasts suggest that A-repeats play crucial biological functions, and their role in humans remains largely unknown. Here, we showed a non-random pattern of distribution of sense A- and T-repeats within 20 kb around transcription start sites (TSSs) in the human genome. Different distributions of these repeats are observed upstream and downstream of TSSs. Sense A-repeats are enriched upstream, whereas sense T-repeats are enriched downstream of TSSs. This enrichment directly correlates with repeat size. Genes with different functions contain different lengths of repeats. In humans, tissue-specific genes are enriched for short repeats of <10 bp, whereas housekeeping genes are enriched for long repeats of ≥10 bp. We demonstrated that DICER1 and Argonaute proteins are required for the cis-regulatory role of A-repeats. Moreover, in the presence of a synthetic polymer that mimics an A-repeat, protein binding to A-repeats was blocked, resulting in a dramatic change in the expression of genes containing upstream A-repeats. Our findings suggest a length-dependent cis-regulatory function of A-repeats and that Argonaute proteins serve as trans-acting factors, binding to A-repeats.
Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand, Inter-Department Program of Biomedical Sciences, Faculty of Graduate School, Chulalongkorn University, Bangkok 10330, Thailand, Department of Electrical and Computer Engineering, Faculty of Engineering, King Mongkut's University of Technology North Bangkok, Bangkok 10800, Thailand, Division of Molecular Genetics, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand and Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
Chatchawit
C
Aporntewan
Piyapat
P
Pin-on
Nachol
N
Chaiyaratana
Monnat
M
Pongpanich
Viroj
V
Boonyaratanakornkit
Apiwat
A
Mutirangura
D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018895:Microsatellite Repeats; D051381:Rats; D050436:Regulatory Elements, Transcriptional; D043244:Ribonuclease III / Q000378:metabolism*; D024363:Transcription Initiation Site
D060565:Argonaute Proteins; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases