Molecular insights into transgenerational non-genetic inheritance of acquired behaviours

Bohacek, Johannes; Mansuy, Isabelle M

doi:10.1038/nrg3964

“…Multigenerational transmission of a nongenetic phenotype is considered transgenerational when it is persistent beyond the epigenetic reprogramming in primordial germ cells (PGCs) (1,2), potentially conveying illness including metabolic diseases, malignancies, reproductive defects, or behavioral alterations (2,4,5). However, this is still a controversial subject due partly to the lack of direct experimental demonstration of transgenerational epigenetic alterations escaping the epigenetic erasure in mammalian PGCs (2,6,7).…”

mentioning

confidence: 99%

Erasure of DNA methylation, genomic imprints, and epimutations in a primordial germ-cell model derived from mouse pluripotent stem cells

Miyoshi

¹

,

Stel

²

,

Shioda

³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The genome-wide depletion of 5-methylcytosines (5meCs) caused by passive dilution through DNA synthesis without daughter strand methylation and active enzymatic processes resulting in replacement of 5meCs with unmethylated cytosines is a hallmark of primordial germ cells (PGCs). Although recent studies have shown that in vitro differentiation of pluripotent stem cells (PSCs) to PGC-like cells (PGCLCs) mimics the in vivo differentiation of epiblast cells to PGCs, how DNA methylation status of PGCLCs resembles the dynamics of 5meC erasure in embryonic PGCs remains controversial. Here, by differential detection of genome-wide 5meC and 5-hydroxymethylcytosine (5hmeC) distributions by deep sequencing, we show that PGCLCs derived from mouse PSCs recapitulated the process of genome-wide DNA demethylation in embryonic PGCs, including significant demethylation of imprint control regions (ICRs) associated with increased mRNA expression of the corresponding imprinted genes. Although 5hmeCs were also significantly diminished in PGCLCs, they retained greater amounts of 5hmeCs than intragonadal PGCs. The genomes of both PGCLCs and PGCs selectively retained both 5meCs and 5hmeCs at a small number of repeat sequences such as GSAT_MM, of which the significant retention of bisulfite-resistant cytosines was corroborated by reanalysis of previously published whole-genome bisulfite sequencing data for intragonadal PGCs. PSCs harboring abnormal hypermethylation at ICRs of the Dlk1-Gtl2-Dio3 imprinting cluster diminished these 5meCs upon differentiation to PGCLCs, resulting in transcriptional reactivation of the Gtl2 gene. These observations support the usefulness of PGCLCs in studying the germline epigenetic erasure including imprinted genes, epimutations, and erasure-resistant loci, which may be involved in transgenerational epigenetic inheritance.

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“…Epigenetics play an central role for the development of cancer cells and cardiovascular diseases and thus determine old-age mortality in humans (Ordovás andSmith, 2010, Jones andBaylin, 2002). Moreover, epigenetic changes influence mental health and cognition with behavioral implications (Bale, 2014, Gräff and Mansuy, 2008, McGowan et al, 2008, Radtke et al, 2011, Bohacek and Mansuy, 2015.…”

Section: Epigenetic Imprintingmentioning

confidence: 99%

Transgenerational effects of childhood conditions on third generation health and education outcomes

Berg

¹

,

Pinger

²

2016

Economics & Human Biology

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Phone: +49-621-181-1923; Fax: +49-228-73-9239. AbstractThis paper examines the extent to which pre-puberty nutritional conditions in one generation affect productivity-related outcomes in later generations. Recent findings from the biological literature suggest that the so-called slow growth period around age 9 is a sensitive period for male germ cell development. We build on this evidence and investigate whether undernutrition at those ages transmits to children and grandchildren. Our findings indicate that third generation males (females) tend to have higher mental health scores if their paternal grandfather (maternal grandmother) was exposed to a famine during the slow growth period. These effects appear to reflect biological responses to adaptive expectations about scarcity in the environment, and as such they can be seen as an economic correctional mechanism in evolution, with marked socio-economic implications for the offspring.

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“…In this context, the possibility of transgenerational transmission is particularly interesting (see e.g. Harper, 2005, Gräff and Mansuy, 2008, Masterpasqua, 2009, Grossniklaus et al, 2013, Bohacek and Mansuy, 2015. Epigenetic imprinting is the phenomenon that shortly after conception, when stem cells are formed, some of the methyl tags from previous generations remain, causing heritable changes in gene functioning that are not driven by changes in the DNA sequence.…”

Section: Epigenetic Imprintingmentioning

confidence: 99%

Transgenerational Effects of Childhood Conditions on Third Generation Health and Education Outcomes

Berg

¹

,

Pinger

²

2014

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Phone: +49-621-181-1923; Fax: +49-228-73-9239. AbstractThis paper examines the extent to which pre-puberty nutritional conditions in one generation affect productivity-related outcomes in later generations. Recent findings from the biological literature suggest that the so-called slow growth period around age 9 is a sensitive period for male germ cell development. We build on this evidence and investigate whether undernutrition at those ages transmits to children and grandchildren. Our findings indicate that third generation males (females) tend to have higher mental health scores if their paternal grandfather (maternal grandmother) was exposed to a famine during the slow growth period. These effects appear to reflect biological responses to adaptive expectations about scarcity in the environment, and as such they can be seen as an economic correctional mechanism in evolution, with marked socio-economic implications for the offspring.

show abstract

Molecular insights into transgenerational non-genetic inheritance of acquired behaviours

Cited by 265 publications

References 119 publications

Erasure of DNA methylation, genomic imprints, and epimutations in a primordial germ-cell model derived from mouse pluripotent stem cells

Erasure of DNA methylation, genomic imprints, and epimutations in a primordial germ-cell model derived from mouse pluripotent stem cells

Transgenerational effects of childhood conditions on third generation health and education outcomes

Transgenerational Effects of Childhood Conditions on Third Generation Health and Education Outcomes

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