Molecular mechanisms of transgenerational epigenetic inheritance

Cavalli, Giacomo; Cavalli, Giacomo

doi:10.1038/s41576-021-00438-5

Cited by 262 publications

(204 citation statements)

References 172 publications

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“…Paternal HFD, leading to diet-induced obesity (DIO) in rats 3 – 5 , results in offspring with delayed growth, impaired liver function 6 – 10 , and deviations in social and anxiety-like defensive behavioral responses 11 , epigenetic reprogramming 12 , 13 , and alterations to the gut microbiome 14 , 15 . Recently, paternal diet has been implicated in the development of inter- and transgenerational offspring phenotypes 16 – 18 . While altered maternal investment 11 , 19 – 21 could potentially explain offspring developmental deficits, epigenetic changes to spermatozoa that cause negative outcomes in the paternal lineage have been identified 22 – 29 .…”

Section: Introductionmentioning

confidence: 99%

Effects of paternal high-fat diet and maternal rearing environment on the gut microbiota and behavior

Korgan

Foxx

Hashmi

et al. 2022

Sci Rep

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Exposing a male rat to an obesogenic high-fat diet (HFD) influences attractiveness to potential female mates, the subsequent interaction of female mates with infant offspring, and the development of stress-related behavioral and neural responses in offspring. To examine the stomach and fecal microbiome’s potential roles, fecal samples from 44 offspring and stomach samples from offspring and their fathers were collected and bacterial community composition was studied by 16 small subunit ribosomal RNA (16S rRNA) gene sequencing. Paternal diet (control, high-fat), maternal housing conditions (standard or semi-naturalistic housing), and maternal care (quality of nursing and other maternal behaviors) affected the within-subjects alpha-diversity of the offspring stomach and fecal microbiomes. We provide evidence from beta-diversity analyses that paternal diet and maternal behavior induced community-wide shifts to the adult offspring gut microbiome. Additionally, we show that paternal HFD significantly altered the adult offspring Firmicutes to Bacteroidetes ratio, an indicator of obesogenic potential in the gut microbiome. Additional machine-learning analyses indicated that microbial species driving these differences converged on Bifidobacterium pseudolongum. These results suggest that differences in early-life care induced by paternal diet and maternal care significantly influence the microbiota composition of offspring through the microbiota-gut-brain axis, having implications for adult stress reactivity.

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Section: Introductionmentioning

confidence: 99%

Effects of paternal high-fat diet and maternal rearing environment on the gut microbiota and behavior

Korgan

Foxx

Hashmi

et al. 2022

Sci Rep

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“…Since mammals reproduce sexually, the epigenetic codes that induce the acquired traits must lie in the gametes, sperm, and eggs. Indeed, epimutations, including changes in sperm DNA methylome (e.g., 5mC), histone modifications, and small RNA profiles, have been associated with various acquired traits in both human and animal models ( 18 , 19 ). However, the causative relationship between specific epimutations (e.g., altered DNA methylation or histone marks) and specific phenotypes has not been established.…”

Section: Introductionmentioning

confidence: 99%

Perinatal Exposure to Nicotine Alters Sperm RNA Profiles in Rats

et al. 2022

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Perinatal exposure to smoking has been associated with childhood asthma, one of the most common pediatric conditions affecting millions of children globally. Of great interest, this disease phenotype appears heritable as it can persist across multiple generations even in the absence of persistent exposure to smoking in subsequent generations. Although the molecular mechanisms underlying childhood asthma induced by perinatal exposure to smoking or nicotine remain elusive, an epigenetic mechanism has been proposed, which is supported by the data from our earlier analyses on germline DNA methylation (5mC) and histone marks (H3 and H4 acetylation). To further investigate the potential epigenetic inheritance of childhood asthma induced by perinatal nicotine exposure, we profiled both large and small RNAs in the sperm of F1 male rats. Our data revealed that perinatal exposure to nicotine leads to alterations in the profiles of sperm-borne RNAs, including mRNAs and small RNAs, and that rosiglitazone, a PPARγ agonist, can attenuate the effect of nicotine and reverse the sperm-borne RNA profiles of F1 male rats to close to placebo control levels.

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“…There has been a concerted effort in recent years to determine how epigenetic inheritance impacts offspring health (e.g. Heard and Martienssen, 2014; Klosin et al, 2017; Tabuchi et al, 2018; Kaneshiro et al, 2019; Fitz-James and Cavalli, 2022). Maternal MES-4’s role in propagating gamete-inherited H3K36me3 patterns through embryogenesis is a clear example of epigenetic inheritance (Kreher et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Maternal H3K36 and H3K27 HMTs protect germline immortality via regulation of the transcription factor LIN-15B

Cockrum

Strome

2022

Preprint

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Maternally synthesized products play critical roles in development of offspring. A premier example is the C. elegans H3K36 methyltransferase MES-4, which is essential for germline survival and development in offspring. How maternal MES-4 protects germline immortality is not well understood, but its role in H3K36 methylation hinted that it may regulate gene expression in Primordial Germ Cells (PGCs). We tested this hypothesis by profiling transcripts from single pairs of PGCs dissected from wild-type and mes-4 mutant (lacking maternal and zygotic MES-4) newly hatched larvae. We found that mes-4 PGCs display normal turn-on of most germline genes and normal repression of somatic genes, but dramatically up-regulate hundreds of genes on the X chromosome. We demonstrated that X mis-expression is the cause of germline death by generating and analyzing mes-4 mutants that inherited different endowments of X chromosome(s). Intriguingly, removal of the THAP transcription factor LIN-15B from mes-4 mutants reduced X mis-expression and prevented germline death. lin-15B is X-linked and mis-expressed in mes-4 PGCs, identifying it as a critical target for MES-4 repression. The above findings extend to the H3K27 methyltransferase MES-2/3/6, the C. elegans version of Polycomb Repressive Complex 2. We propose that maternal MES-4 and PRC2 cooperate to protect germline survival by preventing synthesis of germline-toxic products encoded by genes on the X chromosome, including the key transcription factor LIN-15B.

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Molecular mechanisms of transgenerational epigenetic inheritance

Cited by 262 publications

References 172 publications

Effects of paternal high-fat diet and maternal rearing environment on the gut microbiota and behavior

Effects of paternal high-fat diet and maternal rearing environment on the gut microbiota and behavior

Perinatal Exposure to Nicotine Alters Sperm RNA Profiles in Rats

Maternal H3K36 and H3K27 HMTs protect germline immortality via regulation of the transcription factor LIN-15B

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