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Early Life Experiences Affect Retrotransposon Accumulation in Mouse Brains

NEW YORK (GenomeWeb) – The early life experiences of mouse pups influence the accumulation of retrotransposons within their brains.

Retrotransposons like long interspersed nuclear elements (LINEs) can copy themselves and move from one spot in the genome to another, including within neuronal cells of the brain, and cause somatic mosaicism.

"While we've known for a while that cells can acquire changes to their DNA, it's been speculated that maybe it's not a random process," first author Tracy Bedrosian, formerly of the Salk Institute, said in a statement. "Maybe there are factors in the brain or in the environment that cause changes to happen more or less frequently."

Bedrosian and her colleagues suspected that life experiences like the level of mothering an animal receives while young could lead to those changes. They developed droplet digital PCR (ddPCR) assays to gauge the number of LINE 1 (L1) retrotransposon copies present in mouse samples. Depending on whether the mice tested had nurturing or neglectful mothers, the researchers noted differences in their accumulated L1 levels, as they reported in Science today.

Mouse mothers naturally fall into two groups, ones that provide a high amount of maternal care and ones that do not. Bedrosian and her colleagues observed the level of licking, grooming, and nursing mice provided to their young and then used their ddPCR assays to measure the pups' L1 levels. L1 elements are about 6 kilobases long, and the researchers' four assays targeted different regions of the element.

Mice whose mothers were more attentive had lower L1 levels in their hippocampus than mice whose mothers were inattentive, they found.

The researchers noted that the mice in their study were genetically homogeneous inbred mice and that the L1 copy number was similar among all the mouse pups' parents.

The researchers also found that this L1 accumulation was specific to the hippocampus and did not occur in other tissues like the frontal cortex or heart. The hippocampus of the brain is sensitive to environmental stimuli, is involved in emotion, memory, and some involuntary functions, and is still undergoing cell division and differentiation in young rodents.

Additionally, only L1 retrotransposons appeared to accumulate in these pups; levels of other mobile elements like short interspersed nuclear element B1, SINE B2, and intracisternal A particle elements did not correlate with maternal care.

Bedrosian and her colleagues also swapped pups born to attentive mothers and those born to less attentive ones to find that the level of maternal care pups received, rather than their biological parent, influenced L1 accumulation.

By injecting mice with a marker of cell proliferation, the researchers also followed neurogenesis in the mice to find no difference between the high- and low-maternal care pups.

When they examined methylation of L1 and other mobile element sites — as maternal care has been linked to epigenetic changes — they noticed variation in L1 methylation between pups that experienced different levels of care. No variation was seen at other mobile elements. Mice whose mothers provided low amounts of care had lower methylation along the L1 promoter, particularly at the YY1 binding site. This then led to increased L1 mRNA expression in the hippocampus, and suggested to the researchers that methylation could be linked to element mobility.

"This finding agrees with studies of childhood neglect that also show altered patterns of DNA methylation for other genes," senior author Rusty Gage from the Salk said in a statement. "That's a hopeful thing, because once you understand a mechanism, you can begin to develop strategies for intervention."

However, Columbia University Medical Center's Saera Song and University of California, San Diego's Joseph Gleeson cautioned in a related commentary appearing in Science that the results may not extend to people. L1, they noted, is more active in the rodent brain than it is in the human brain, and there are many more active L1 elements in the rodent genome, between 3,000 and 4,000, than in the human genome, between 80 and 100.

"Additionally, we still do not completely understand the biological and physiological consequences of L1 retrotransposition events," Song and Gleeson wrote.