Developmentally regulated extended domains of DNA hypomethylation encompass highly transcribed genes of the human beta-globin locus.
OBJECTIVE
DNA methylation has long been implicated in developmental beta-globin gene regulation. However, the mechanism underlying this regulation is unclear, especially because these genes do not contain CpG islands. This has led us to propose and test the hypothesis that, just as for histone modifications, developmentally specific changes in human beta-like globin gene expression are associated with long-range changes in DNA methylation.


METHODS
Bisulfite sequencing was used to determine the methylation state of individual CpG dinucleotides across the beta-globin locus in uncultured primary human erythroblasts from fetal liver and bone marrow, and in primitive-like erythroid cells derived from human embryonic stem cells.


RESULTS
beta-globin locus CpGs are generally highly methylated, but domains of DNA hypomethylation spanning thousands of base pairs are established around the most highly expressed genes during each developmental stage. These large domains of DNA hypomethylation are found within domains of histone modifications associated with gene expression. We also find hypomethylation of a small proportion of gamma-globin promoters in adult erythroid cells, suggesting a mechanism by which adult erythroid cells produce fetal hemoglobin.


CONCLUSIONS
This is one of the first reports to show that changes in DNA methylation patterns across large domains around non-CpG island genes correspond with changes in developmentally regulated histone modifications and gene expression. These data support a new model in which extended domains of DNA hypomethylation and active histone marks are coordinately established to achieve developmentally specific gene expression of non-CpG island genes.
Lathrop
Melissa J
MJ
Departments of Microbiology/Immunology and Genetics, and Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH 03756, USA.
Hsu
Mei
M
Richardson
Christine A
CA
Olivier
Emmanuel N
EN
Qiu
Caihong
C
Bouhassira
Eric E
EE
Fiering
Steven
S
Lowrey
Christopher H
CH
D018899:CpG Islands; D019175:DNA Methylation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D055544:beta-Globins / Q000235:genetics*
D055544:beta-Globins