Large hypomethylated domains serve as strong repressive machinery for key developmental genes in vertebrates

Abstract

DNA methylation is a fundamental epigenetic modification in vertebrate genomes and a small fraction of genomic regions is hypomethylated. Previous studies have implicated hypomethylated regions in gene regulation, but their functions in vertebrate development remain elusive. To address this issue, we generated epigenomic profiles that include base-resolution DNA methylomes and histone modification maps from both pluripotent cells and mature organs of medaka fish and compared the profiles with those of human ES cells. We found that a subset of hypomethylated domains harbor H3K27me3 (K27HMDs) and their size positively correlates with the accumulation of H3K27me3. Large K27HMDs are conserved between medaka and human pluripotent cells and predominantly contain promoters of developmental transcription factor genes. These key genes were found to be under strong transcriptional repression, when compared with other developmental genes with smaller K27HMDs. Furthermore, human-specific K27HMDs show an enrichment of neuronal activityrelated genes, which suggests a distinct regulation of these genes in medaka and human. In mature organs, some of the large HMDs become shortened by elevated DNA methylation and associate with sustained gene expression. This study highlights the significance of domain size in epigenetic gene regulation. We propose that large K27HMDs play a crucial role in pluripotent cells by strictly repressing key developmental genes, whereas their shortening consolidates long-term gene expression in adult differentiated cells.

Dynamics of DNA methylomes underlie oyster development

“…It implies stabilisation of open chromatin states at loci of cleavage genes that lie within DMRs during oyster development. Conversely, persistent unmethylated regions could be of functional significance for developmental gene silencing [40] as reflected by the strong repression of unmethylated genes (Fig 3A). The primary resemblance with oocyte DNA methylation patterns (Fig 1) suggests that these loci could be inherited, their transcription being further regulated by local methylation dynamics in the embryo, reminiscent of recent findings in the mouse [41].…”

Tet1 and Tet2 Protect DNA Methylation Canyons against Hypermethylation

“…Because the deficiency of Tet1 also led to significant, albeit weaker, hypermethylation in the same regions, we suggest an additive and collaborative role for both enzymes, at least in the regions we analyzed. Lineage-specific genes residing in hypomethylated domains appear to be mostly regulated by chromatin modifications and not directly by DNA methylation (1,15,44). Canyon collapse in Tet-deficient cells then leads to the disruption of this chromatin-based transcription-regulatory network.…”

LSD1/KDM1A promotes hematopoietic commitment of hemangioblasts through downregulation of Etv2

“…ChIP analysis was basically carried out as described previously (66,67) using specific antibodies: anti-monoMeK4H3 (ab8895; Abcam), anti-diMeK4H3 (UP07-030; Upstate), and anti-triMeK4H3 (ab8580; Abcam). Two hundred fifty embryos were used for each assay, and cells were sonicated by a Branson Sonifier 250.…”