Abstract
The human genome contains ∼30,000 CpG islands (CGIs). While CGIs associated with promoters nearly always remain unmethylated, many of the ∼9,000 CGIs lying within gene bodies become methylated during development and differentiation. Both promoter and intragenic CGIs may also become abnormally methylated as a result of genome rearrangements and in malignancy. The epigenetic mechanisms by which some CGIs become methylated but others, in the same cell, remain unmethylated in these situations are poorly understood. Analyzing specific loci and using a genome-wide analysis, we show that transcription running across CGIs, associated with specific chromatin modifications, is required for DNA methyltransferase 3B (DNMT3B)-mediated DNA methylation of many naturally occurring intragenic CGIs. Importantly, we also show that a subgroup of intragenic CGIs is not sensitive to this process of transcription-mediated methylation and that this correlates with their individual intrinsic capacity to initiate transcription in vivo. We propose a general model of how transcription could act as a primary determinant of the patterns of CGI methylation in normal development and differentiation, and in human disease.
Highlights
The human genome contains ∼30,000 CpG islands (CGIs)
We have previously shown that silencing of HBA2 expression on the rearranged allele of an individual (ZF) with α-thalassemia is caused by de novo DNA methylation of the HBA promoter CGI in the presence of antisense transcription from the truncated LUC7L gene [10] (Fig. 1)
Analyzing EBV-transformed lymphocytes from ZF (EBV-ZF) and a normal individual (EBV-RN), we found no differences in the levels of H3K4me3 (Fig. 2A, Left)
Summary
While CGIs associated with promoters nearly always remain unmethylated, many of the ∼9,000 CGIs lying within gene bodies become methylated during development and differentiation Both promoter and intragenic CGIs may become abnormally methylated as a result of genome rearrangements and in malignancy. To address how transcription running across a CGI may determine whether or not it becomes methylated, we took an experimental approach to study in detail the mechanism by which a CGI located at the α-globin locus becomes methylated when incorporated into a newly formed transcriptional unit causing a human disease [α-thalassemia [10]] (Fig. 1) To relate these findings to endogenous intragenic CGIs, we analyzed a previously described, naturally occurring CGI associated with the rhomboid 5 homolog 1. We experimentally determined the order in which these events
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
