The team focused on the H19 gene locus, which was previously shown to be controlled by the H19 imprinted control region (ICR) via genomic imprinting. The paternal H19 ICR is modified via DNA methylation while the maternal H19 ICR allele isn’t methylated. Methylation of the H19 ICR is in part responsible for repressing the expression of H19. However, H19 itself can also be methylated, and the effects of this had yet to be clarified.

“While the general imprinting mechanism for the mouse H19 locus is well established, it is less clear how expression of H19 is affected by its own methylation status,” explains Assistant Professor Hitomi Matsuzaki, lead author of the study. “Our previous finding suggested that the methylation state of the H19 ICR is transferred directionally downstream to H19 in the fertilized embryo post-implantationwhich makes it difficult to study the two in isolation.”

Then, the team hypothesized that by inverting the H19 ICR, thus reversing its direction, they could reduce H19 methylation and they created mutant mice to test this. Interestingly, with paternally inherited inverted ICR, H19 had decreased levels of methylation and as a result was derepressed. However, when the same experiments were conducted for the maternally inherited inverted ICR, H19 expression levels were lower compared with the un-inverted ICR allele, despite having low methylation.

“Our findings involving the maternally inherited allele were quite unexpected, especially given the paternal data,” describes Assistant Professor Matsuzaki. “We did observe slightly more ICR methylation in the inverted allele compared with the wild type one.”

Further work did not provide evidence that ICR methylation status was responsible for the differential H19 expression in the maternally inherited alleles. Collectively, these data suggest that, for maternal inheritance, H19 expression is in fact affected by the ICR orientation, but it is independent of DNA methylation.

Overall, Assistant Professor Matsuzaki and colleagues provided compelling insights into the complex nature of genomic imprinting in mice. The methylation status and direction of certain DNA sequences can affect genes found at the locus in different manners, and the effects also vary based on which parent the allele was inherited from. These results shed new light on the current knowledge and raise intriguing questions to be addressed by further studies.

This work was supported in parts by JSPS KAKENHI grants (grant numbers JP20K06481 to H.M., JP19H03134 to K.T., and JP20K21360 to K.T.), MEXT KAKENHI grants (grant number JP20H05379 to H.M.), and a research grant from the Takeda Science Foundation to K.T.

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