倒装语序:你的方向DNAmay be as important as which parent it came from

Date:: January 4, 2022
Source:: University of Tsukuba
Summary:: Researchers generated mice with a specific DNA sequence inverted to determine if orientation affects expression of a gene called H19. Expression can also be impacted if the surrounding DNA is altered by a process called methylation. Interestingly, methylation was only relevant when the inverted sequence was inherited from the father. When inherited from the mother, the inversion had the opposite effect on H19 expression, suggesting a more complex mechanism is at play.
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FULL STORY

Mammalian offspring inherit two versions, or alleles, of each gene with one allele from each biological parent. However, gene expression is tightly regulated and certain genes undergo the phenomenon of "genomic imprinting," which is where only the allele received by the male or the female parent is expressed. Imprinted genes play diverse roles in development and disruption of their mono-allelic expression can cause diseases, thus understanding the mechanisms behind their regulation is critical. In a recent article published inCommunications Biology, a team led by researchers at the University of Tsukuba examined genomic imprinting of a specific genetic locus in mice. Their experiments helped reveal the molecular details of how this mechanism governs expression levels of these genes.

The team focused on theH19gene locus, which was previously shown to be controlled by theH19imprinted control region (ICR) via genomic imprinting. The paternalH19ICR is modified via DNA methylation while the maternalH19ICR allele isn't methylated. Methylation of theH19ICR is in part responsible for repressing the expression ofH19.However,H19itself can also be methylated, and the effects of this had yet to be clarified.

"While the general imprinting mechanism for the mouseH19locus is well established, it is less clear how expression ofH19is 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 theH19ICR is transferred directionally downstream toH19in the fertilized embryo post-implantationwhich makes it difficult to study the two in isolation."

Then, the team hypothesized that by inverting theH19ICR, thus reversing its direction, they could reduceH19methylation and they created mutant mice to test this. Interestingly, with paternally inherited inverted ICR,H19had decreased levels of methylation and as a result was derepressed. However, when the same experiments were conducted for the maternally inherited inverted ICR,H19expression 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 differentialH19expression in the maternally inherited alleles. Collectively, these data suggest that, for maternal inheritance,H19expression 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.