title: Effects of cytosine methylation on transcription factor binding sites.
abstract: BACKGROUND
  DNA methylation in promoters is closely linked to downstream gene repression. However, whether DNA methylation is a cause or a consequence of gene repression remains an open question. If it is a cause, then DNA methylation may affect the affinity of transcription factors (TFs) for their binding sites (TFBSs). If it is a consequence, then gene repression caused by chromatin modification may be stabilized by DNA methylation. Until now, these two possibilities have been supported only by non-systematic evidence and they have not been tested on a wide range of TFs. An average promoter methylation is usually used in studies, whereas recent results suggested that methylation of individual cytosines can also be important.
  
  
  RESULTS
  We found that the methylation profiles of 16.6% of cytosines and the expression profiles of neighboring transcriptional start sites (TSSs) were significantly negatively correlated. We called the CpGs corresponding to such cytosines "traffic lights". We observed a strong selection against CpG "traffic lights" within TFBSs. The negative selection was stronger for transcriptional repressors as compared with transcriptional activators or multifunctional TFs as well as for core TFBS positions as compared with flanking TFBS positions.
  
  
  CONCLUSIONS
  Our results indicate that direct and selective methylation of certain TFBS that prevents TF binding is restricted to special cases and cannot be considered as a general regulatory mechanism of transcription.
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Medvedeva
authors.forename: Abdullah M
authors.initials: AM
authors.lastname: Khamis
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Kulakovskiy
authors.forename: Wail
authors.initials: W
authors.lastname: Ba-Alawi
authors.forename: Md Shariful I
authors.initials: MS
authors.lastname: Bhuyan
authors.forename: Hideya
authors.initials: H
authors.lastname: Kawaji
authors.forename: Timo
authors.initials: T
authors.lastname: Lassmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Harbers
authors.forename: Alistair R R
authors.initials: AR
authors.lastname: Forrest
authors.affiliation: Computational Bioscience Research Center, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia. vladimir.bajic@kaust.edu.sa.
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Bajic
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D019295:Computational Biology; D018899:CpG Islands; D003596:Cytosine / Q000737:chemistry / Q000378:metabolism*; D019175:DNA Methylation; D006801:Humans; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D024363:Transcription Initiation Site
chemical_list: D014157:Transcription Factors; D003596:Cytosine