Sometimes it’s best to get straight to the point, so let’s dive into this study of DNA methyltransferase 3a (DNMT3A) isoforms with variable lengths, which reveals a chromatin interaction domain that regulates bivalent gene expression and supports early postnatal survival in mice!
Previous studies that didn’t beat around the bush described how postnatal development requires the activity of DNMT3A, which comes in two isoforms with unknown individual functions: a long DNMT3A1 isoform and a shorter DNMT3A2 isoform lacking a 219 amino acid intrinsically disordered N-terminal domain. To understand these mysterious differences, a team led by Margaret A. Goodell (Baylor College of Medicine) profiled the function of DNMT3A isoforms during mouse development.
Let’s cut to the chase and hear the long and short of this new DNA methylation-based study from Gu, Hao, and colleagues:
- Analyses of DNMT3A isoform-specific knock out (KO) mouse models demonstrate the requirement for the long DNMT3A1 isoform (but not the short DNMT3A2 isoform) for postnatal development (after around 23 days)
- High expression levels in postnatal neurons allow DNMT3A1 to bind near DNA methylation “valleys” and regulate the expression of bivalent neurodevelopmental genes via DNA methylation
- DNMT3A1 KO reduces the expression of said genes, which correlates with impaired synaptic plasticity
- DNMT3A1 restoration in the nervous system partially rescues perinatal lethality caused by Dnmt3a1 knockout, suggesting the need for the brain-specific expression of the long DNMT3A1 isoform for postnatal viability
- Deletion of the DNMT3A1 N-terminal domain (resulting in short DNMT3A2 isoform expression in the brain) prompts the onset of neurological deficits (thereby disrupting mouse development) and the loss of DNMT3A1 localization to bivalent target genes
- Interestingly, a ubiquitin-interacting motif embedded in a putative α-helix of the DNMT3A1 N-terminal domain binds to K119 ubiquitinated H2A-modified nucleosomes (H2AK119ub)
- This interaction enables DNMT3A1 recruitment to Polycomb-regulated regions
- Therefore, the N-terminal domain acts as a chromatin “reader” to mediate DNMT3A1 recruitment to bivalent target genes and regulate DNA methylation and gene expression
To get straight to the point, these data provide evidence for an isoform-specific role for DNMT3A1 in postnatal mouse development, with the N-terminal domain supporting chromatin interactions, gene expression alterations, and functional consequences in the developing nervous system. In the future, the authors believe that the DNMT3A1 N-terminal domain may be able to modulate DNA methylation alterations associated with human cancers or growth disorders.
For both the long and the short of this exciting new study, see Nature Genetics, May 2022.