While some research develops at “a snail’s pace,” other projects “canter” along briskly; however, a recent study moved faster than a rat up a drainpipe, with a cross-country team leaving their mark on the “rat race” by successfully identifying novel imprinted genes and highlighting the rapid evolution of imprinting in this vital model animal.
A globe-encompassing team led by Matthew Lorincz and Hisato Kobayashi performed low-input RNA sequencing and whole genome bisulfite sequencing in extraembryonic and embryonic tissues from post-implantation Norway brown rat embryos at allele-specific resolution to systematically identify novel imprinted genes. They employed reciprocal F1 hybrids as the gold standard in the genome-wide search for imprinted genes, of which only 13 have been identified in rats based on homology with mouse/human orthologs.
Let’s hear how Albert and colleagues identified rat imprinted genes/genomic imprints and demonstrated how the evolution of imprinting has raced along:
- They identify 14 and 26 imprinted genes in embryonic and extraembryonic rat tissues, respectively, with 10 imprinted genes shared between tissues
- 22 display conservation with the mouse, with 8 representing novel rat-specific candidate imprinted genes (Zfp516, Slc38a1, Zfp64, Gsto1, Rpl39l, Syt16AS, Gadl1-3’UTR, and LOC108350526)
- The presence of many of these 8 genes in extraembryonic rat tissues finding agrees with the more rapid evolution of extraembryonic imprinting
- Comparisons of rats and mice (diverged only around 13 million years ago) demonstrate the conservation of canonical genomic imprints (allele-specific DNA methylation) in the embryo; however, the evolution of imprinting raced along, with divergent non-canonical imprinting (allele-specific histone modifications) seen in extraembryonic tissue
- Only 3 paternally-expressed imprinted genes display conservation in the extraembryonic tissue, which all use non-canonical H3K27me3 imprinting (as evaluated by CUT&RUN assay)
- Analysis of rat oocytes suggests that the species-specific deposition of H3K27me3 explains divergent non-canonical imprinting of some genes in extraembryonic tissues
- Meta-analysis of rat-specific imprinted genes reveals mechanisms that establish species-specific imprinted expression, which include
- the appearance of ZFP57 binding motifs through single-nucleotide substitutions
- the insertion of endogenous retroviral promoters subject to maternal-specific methylation after fertilization
- H3K27me3 deposition in the oocyte
Co-senior author Matthew Lorincz shares, “This first reported genome-wide catalog of imprinted genes and genomic imprints in the rat embryo and extraembryonic tissue and concomitant comparison to imprinting in the mouse reveal important insights into the evolution of intergenerational epigenetic inheritance mechanisms, including a surprisingly rapid rate of evolution of non-canonical imprinting in murids. The novel list of imprinted genes identified in the rat will hopefully promote further study of the mechanisms of establishment and relevance of such imprinting in this increasingly utilized model organism.”
This sprint session provides an “atlas” of genomic imprinting and reveals the recent and rapid evolutionary divergence of non-canonical imprinting; however, this “rat” race will continue at longer distances. Future marathon sessions may explore links between non-canonical imprinting and fetal/placental growth, measure the extent/conservation of imprinted gene expression in other mammals, and review the role of imprinted genes in behavior/other traits in the tractable rat model.
For more on how these speedy researchers left their mark on the rat race, see Genome Biology, March 2023.