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element (SINE) B1, SINE B2, and intracisternal A
that compensated for separation (Fig. 2D). In YY1 transcription factor binding site required for maternal care had less methylation across the L1
addition, we performed a cross-fostering exper- L1 gene expression (Fig. 3A) (16). Using bisulfite promoter (Fig. 3C), particularly at the YY1 bind-
iment in which two to four pups from each litter sequencing, we assessed a region of 13 individual ing site (Fig. 3D). This difference corresponded
were reared by a foster dam beginning at PND 0. CpGs containing the YY1 binding site to deter- to more L1 mRNA expression in the hippocam-
L1 3′UTR copy number was better correlated mine the average methylation level in the hippo- pus at PND 4 (Fig. 3E) but not in the frontal
with the maternal care of the dam that reared campus (Fig. 3B). Mice that experienced low cortex (fig. S7). To investigate how maternal care,
the pups and not with the care of the biological
dam (Fig. 2E).
To examine the mechanism whereby maternal
care affects L1 copy number, we analyzed the rate
of neurogenesis. Stimuli that enhance neurogenesis
may promote retrotransposition because dividing
cells are permissive to the L1 ribonucleoprotein
complex entering the nucleus. We injected mice
daily, for the first 7 days of life, with EdU, a marker
of cell proliferation. Then we collected the hippo-
campi at PND 21 and used flow cytometry to
quantify cells expressing EdU and Prox1, a marker
of dentate granule neurons. Mice reared with
high or low maternal care had similar numbers
of EdU+/Prox1+ neurons and EdU+/Prox1– cells,
brain to be <0.6 to 13 insertions per neuron, de- early life experience can drive structural varia- 6. F. A. Champagne, D. D. Francis, A. Mar, M. J. Meaney,
pending on the brain region and detection method tion of the genome via L1 retrotransposons. Physiol. Behav. 79, 359–371 (2003).
7. N. G. Coufal et al., Nature 460, 1127–1131 (2009).
(19, 20). Mice have thousands more active copies
8. J. K. Baillie et al., Nature 479, 534–537 (2011).
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16. S. H. Lee, S. Y. Cho, M. F. Shannon, J. Fan, D. Rangasamy, A. Paquola, I. Gallina, D. Reid, and S. Linker for technical Competing interests: None declared. Data and materials
PLOS ONE 5, e11353 (2010). assistance and discussions; and the Salk Institute Functional availability: All data needed to evaluate the conclusions
17. J. A. Erwin, M. C. Marchetto, F. H. Gage, Nat. Rev. Neurosci. 15, Genomics Core, Next Generation Sequencing Core, and in the paper are present in the paper or the supplementary
497–506 (2014). Flow Cytometry Core facilities for equipment and technical materials.
18. J. V. Moran, R. J. DeBerardinis, H. H. Kazazian Jr., Science 283, assistance. Funding: This work was supported by NIH
1530–1534 (1999). R01 MH095741, NIH U01 MH106882, The G. Harold and SUPPLEMENTARY MATERIALS
19. G. D. Evrony et al., Cell 151, 483–496 (2012). Leila Y. Mathers Charitable Foundation, The Leona M. and
20. K. R. Upton et al., Cell 161, 228–239 (2015). www.sciencemag.org/content/359/6382/1395/suppl/DC1
Harry B. Helmsley Charitable Trust grant 2012-PG-MED00, The
21. D. Nätt, I. Johansson, T. Faresjö, J. Ludvigsson, A. Thorsell, Materials and Methods
Engman Foundation, Annette C. Merle-Smith, Takeda
Clin. Epigenetics 7, 91 (2015). Figs. S1 to S9
Pharmaceutical International, The JPB Foundation, NIH F32
22. B. Misiak et al., Epigenomics 7, 1275–1285 (2015). Table S1
MH102983 (T.A.B), and a National Alliance for Research
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on Schizophrenia and Depression Young Investigator Award
ACKN OW LEDG MEN TS (T.A.B.). Author contributions: T.A.B. and F.H.G. designed the 12 June 2016; resubmitted 4 November 2017
The authors thank M. L. Gage for critical reading of the experiments and wrote the manuscript. T.A.B., N.N., and Accepted 25 January 2018
manuscript; Q. Zhu for the minor satellite assay; J. Erwin, C.Q. performed the experiments and analyzed the data. 10.1126/science.aah3378
SUPPLEMENTARY http://science.sciencemag.org/content/suppl/2018/03/21/359.6382.1395.DC1
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RELATED http://science.sciencemag.org/content/sci/359/6382/1330.full
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