Our work raises the question of
Our work raises the question of how a mechanism for control of developmental potency based on TEs might have evolved. Active TEs are under acute surveillance by cellular pathways that minimize transposition, including by Kap1 (Rowe et al., 2010). In part because of this, and in part because of a loss in ability to transpose due to an accumulation of mutations, the sequence of TEs is generally thought to be subject to a rapid rate of divergence. In fact, some mammalian species may have completely lost all retrotransposition-competent LINE1 elements in their genome, even though they can still express mutated LINE1 RNAs (Cantrell et al., 2008). Our results indicate that chromatin-associated LINE1 RNA regulates gene expression and developmental potency without requiring retrotransposition activity. This role of LINE1 as a chromatin-associated RNA therefore avoids the potential detrimental effects of LINE1 retrotransposition that have been reported in several disease states, including cancer (Burns, 2017). The interaction of LINE1 RNA with binding partners, such as Nucleolin is expected to be mediated by RNA secondary structure, which is less constrained by primary sequence than protein-coding regions. Thus, rather than being a vulnerability, the regulation of early development by TEs may allow both robustness, due to the repeated nature of TEs, and adaptability, due to their rapid 3CAI and their potential to support transposition in conditions of stress. In this regard, it is interesting that the percentage of the genome occupied by LINE1 elements seems to have sharply increased with development of therian mammals (e.g., Ivancevic et al. ). The exploration of the function of LINE1 in other species should shed light on the role of TEs in shaping the evolution of development.
Acknowledgments We thank J. Boeke for the LINE1 CAG-ORFeus GF-P plasmid, W. An for the cytomegalovirus (CMV) 5′ UTR-ORFeus GF-P plasmid, and D. He for technical assistance with RIP-qPCR. We are grateful to R. Blelloch, M. Conti, and D. Lim and members of the Santos lab for input or for critically reading the manuscript. We thank D. O’Carroll for the LINE1 ORF1p antibody and D. Trono for the CreERT2;Kap1fl/fl ESCs. C.-J.L. thanks R. Smith for managing the mouse colony and technical support, B. Nashun for the Dnase I-TUNEL assay protocol, and D. Soong for setting scanning conditions for confocal microscopy. C.-J.L. is a Royal Society of Edinburgh Personal Research Fellow funded by the Scottish Government. Animal work partially undertaken in the MRC Centre for Reproductive Health, University of Edinburgh was funded by an MRC Centre grant (MR/N022556/1) (to C.-J.L.). X.S. and Y.Y. were supported by grants from the National Natural Science Foundation of China (31471219 and 31630095). B.H. is a Chan Zuckerberg Biohub Investigator. This work was supported by a CIRM postdoctoral fellowship (TG2-01153) (to M.P.), a CIRM Bridges Fellowship (to G.A.P.), a W.M. Keck Foundation Medical Research Grant (to B.H.), NIH grants (R01GM113014 and R01GM123556) (to M.R.-S.), and a pilot grant from the UCSF Resource Allocation Program (to M.R.-S.).
Introduction Reproduction by parthenogenesis or gynogenesis is widespread among vertebrates such as reptiles, fish, and amphibians but does not exist in mammals (Neaves and Baumann, 2011). In the 1980s, elegant pronuclear transplantation experiments performed by the Solter and Surani laboratories suggested that mouse development required both maternal and paternal contributions, which implied the presence of genetic asymmetries of two parental chromosomes (Barton et al., 1984, McGrath and Solter, 1983, McGrath and Solter, 1984, Surani and Barton, 1983, Surani et al., 1984). To study the genetic asymmetries on chromosomes, Cattanach, Searle, and colleagues analyzed offspring with uniparental disomies for specific regions that were generated by mating mice that were heterozygous for Robertsonian or balanced translocations (Cattanach and Kirk, 1985, Searle and Beechey, 1978). The uniparental duplications, resulting in severe embryonic defects or lethality, are distributed over seven chromosomes as 11 segments: proximal and distal chromosome 2 (chr2); proximal chr6; proximal, central, and distal chr7; proximal chr11; distal chr12; proximal and distal chr17; and proximal chr18 (Berger and Epstein, 1989, Cattanach, 1986, Cattanach et al., 1996, Cattanach and Jones, 1994, Cattanach and Kirk, 1985, Cattanach and Rasberry, 1993, Johnson, 1974, Searle and Beechey, 1978, Searle and Beechey, 1990). A decade after the first genetic experiment, three imprinted genes were identified by molecular characterization of the genetic asymmetrical chromosome regions (Barlow et al., 1991, Bartolomei et al., 1991, Ferguson-Smith et al., 1991). To date, approximately 100 imprinted genes have been described in mammals (Bartolomei and Ferguson-Smith, 2011).