CpG Hypomethylation in a Large Domain Encompassing the Embryonic β-Like Globin Genes in Primitive Erythrocytes

Abstract

There is little evidence addressing the role of CpG methylation in transcriptional control of genes that do not contain CpG islands. This is reflected in the ongoing debate about whether CpG methylation merely suppresses retroelements or if it also plays a role in developmental and tissue-specific gene regulation. The genes of the ␤-globin locus are an important model of mammalian developmental gene regulation and do not contain CpG islands. We have analyzed the methylation status of regions in the murine ␤-like globin locus in uncultured primitive and definitive erythroblasts and other cultured primary and transformed cell types. A large (ϳ20-kb) domain is hypomethylated only in primitive erythroid cells; it extends from the region just past the locus control region to before ␤-major and encompasses the embryonic genes Ey, ␤h1, and ␤h0. Even retrotransposons in this region are hypomethylated in primitive erythroid cells. The existence of this large developmentally regulated domain of hypomethylation supports a mechanistic role for DNA methylation in developmental regulation of globin genes.

Developmentally regulated extended domains of DNA hypomethylation encompass highly transcribed genes of the human β-globin locus

“…Recently, we have demonstrated that large domains of DNA hypomethylation are present in the mouse β-globin locus [32], and that developmental changes in γ- and β-globin gene methylation extend beyond the promoter cores [12]. These factors led us to consider whether DNA methylation may influence β-globin locus gene expression through a combinatorial mechanism involving domains of DNA hypomethylation and domains of histone modifications.…”

Prevention of Transcriptional Silencing by a Replicator-Binding Complex Consisting of SWI/SNF, MeCP1, and hnRNP C1/C2

“…LCR-mediated silencing is accompanied by changes in replication timing, DNA methylation, and histone modifications (28,(49)(50)(51). The LCR is required for DNA methylation at ectopic sites (11).…”

Crosstalk between histone modifications maintains the developmental pattern of gene expression on a tissue-specific locus

“…MLL2 contains a CxxC domain, which mediates binding to non-methylated CpG-rich DNA, 89,90 however the region between the LCR and β maj promoter is quite heavily DNA methylated in adult cells. 46 While it has been proposed that MLL2 could bind to methylated H3K4 through its PHD domains, 91 H3K4me2, 27 and H3K4me3, 21 marks are not continuous across the β-globin locus in adult cells. Therefore, it is unlikely that MLL2 uses these domains for self-propagation.…”

“…It is possible that a similar PRMT5/ DNMT3A-mediated process is involved in the formation of DNA hypermethylated domains at the embryonic genes in definitive murine erythroid cells. 46 In addition to histone methylation, nucleosome remodeling and histone deacetylation are likely important for maintaining the mouse embryonic gene in a repressed state, in a similar fashion to the repression of human fetal γ-globin gene, where the transcription factors BCL11A, 47 GATA-1, FOG-1, 47,48 and Ikaros 49 are involved in silencing γ-globin through a mechanism linked to NuRD complex component (Mi-2 and HDAC1) recruitment to the γ-globin gene promoters. 48,49 Notably, in mouse erythroid cells BCL11A forms a complex with all NuRD components, suggesting that this mechanism might be conserved between mouse and human adult erythroid cells.…”