Intragenic DNA methylation prevents spurious transcription initiation

Abstract

In mammals, DNA methylation occurs mainly at CpG dinucleotides. Methylation of the promoter suppresses gene expression, but the functional role of gene-body DNA methylation in highly expressed genes has yet to be clarified. Here we show that, in mouse embryonic stem cells, Dnmt3b-dependent intragenic DNA methylation protects the gene body from spurious RNA polymerase II entry and cryptic transcription initiation. Using different genome-wide approaches, we demonstrate that this Dnmt3b function is dependent on its enzymatic activity and recruitment to the gene body by H3K36me3. Furthermore, the spurious transcripts can either be degraded by the RNA exosome complex or capped, polyadenylated, and delivered to the ribosome to produce aberrant proteins. Elongating RNA polymerase II therefore triggers an epigenetic crosstalk mechanism that involves SetD2, H3K36me3, Dnmt3b and DNA methylation to ensure the fidelity of gene transcription initiation, with implications for intragenic hypomethylation in cancer.

Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis

“…This may reflect the ability of SETD2 to influence transcription elongation and initiation (5,9). Regardless of the molecular mechanisms, loss of SETD2 has been shown to modulate AS in multiple biological contexts.…”

“…Cell culture-based studies demonstrate the defects in chromosome segregation, DNA repair, and reduced nucleotide pools in SETD2-depleted cells (6)(7)(8). Mechanistic characterizations reveal that SETD2-mediated H3K36me3 regulates the recruitment of and DNMT3b to ensure the fidelity of gene transcription initiation in embryonic stem (ES) cells (9). In addition, SETD2 and H3K36me3 are implicated in RNA splicing during gene transcription (10)(11)(12)(13).…”

SETD2: a complex role in blood malignancy

“…H3K36me3 also recruits DNMT3B, leading to the dense methylation of gene bodies, which reinforces intragenic silencing. 2 In addition, H3K36me3 helps direct the splicing machinery to intron/exon boundaries.…”

“…Solutions having the same osmolarity are isotonic. 2,3 Water in pools and rivers is hypotonic compared with sea water, but water from the Dead Sea is hypertonic. Swimming in the ocean or sea is relatively easier than swimming in a pool or river due to the buoyancy of seawater, which contains ;3.5% salt.…”

DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line

“…Moreover, transcriptionally active genes are normally hypermethylated in the gene body (Ball et al 2009, Lister et al 2009). This methylation is thought to block the initiation of spurious transcription, thereby avoiding the generation of aberrant RNAs (Huh et al 2013, Baubec et al 2015, Neri et al 2017. In addition, exons display higher methylation levels than introns, also linking Figure 2 Schematic mechanisms of transcriptional regulation through promoter DNA methylation.…”