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Cited by 19Epigenetics and DNA MethylationGenetic Syndromes and ImprintingBirth, Development, and Health

Characterization of genomic regions escaping epigenetic reprogramming in sheep

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Braz, Camila U, Passamonti, Matilde Maria, Khatib, Hasan·2024·Environmental Epigenetics
DOI 10.1093/eep/dvad010PMC PMC10944287
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Abstract

The mammalian genome undergoes two global epigenetic reprogramming events during the establishment of primordial germ cells and in the pre-implantation embryo after fertilization. These events involve the erasure and re-establishment of DNA methylation marks. However, imprinted genes and transposable elements (TEs) maintain their DNA methylation signatures to ensure normal embryonic development and genome stability. Despite extensive research in mice and humans, there is limited knowledge regarding environmentally induced epigenetic marks that escape epigenetic reprogramming in other species. Therefore, the objective of this study was to examine the characteristics and locations of genomic regions that evade epigenetic reprogramming in sheep, as well as to explore the biological functions of the genes within these regions. In a previous study, we identified 107 transgenerationally inherited differentially methylated cytosines (DMCs) in the F1 and F2 generations in response to a paternal methionine-supplemented diet. These DMCs were found in TEs, non-repetitive regions, and imprinted and non-imprinted genes. Our findings suggest that genomic regions, rather than TEs and imprinted genes, have the propensity to escape reprogramming and serve as potential candidates for transgenerational epigenetic inheritance. Notably, 34 transgenerational methylated genes influenced by paternal nutrition escaped reprogramming, impacting growth, development, male fertility, cardiac disorders, and neurodevelopment. Intriguingly, among these genes, 21 have been associated with neural development and brain disorders, such as autism, schizophrenia, bipolar disease, and intellectual disability. This suggests a potential genetic overlap between brain and infertility disorders. Overall, our study supports the concept of transgenerational epigenetic inheritance of environmentally induced marks in mammals.

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  • These RNA-mediated pathways influence neurodevelopmental, metabolic, and stress-related phenotypes in offspring in animal models.

    “These RNA-mediated pathways influence neurodevelopmental, metabolic, and stress-related phenotypes in offspring in animal models.”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [139]

    The Introduction describes environmentally altered epigenetic marks affecting next-generation phenotypes in mouse models, and the Results and discussion links sperm DNA-methylation regions to genes involved in neural development, growth, and cardiometabolic functions. But the paper examines DNA methylation and gene expression; its RNA sequencing of sperm does not establish that RNA-mediated pathways influence neurodevelopmental, metabolic, and stress-related phenotypes in offspring. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Germline transmission of trauma-related effects may involve a combination of incomplete epigenetic erasure and RNA-mediated signaling mechanisms.

    “Such findings suggest that germline transmission of trauma-related effects may involve a combination of incomplete epigenetic erasure and RNA-mediated signaling mechanisms, offering a biologically plausible framework despite extensive reprogramming.”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [139]

    The Introduction says that epigenetic marks escaping reprogramming may transmit parental experiences and reports sperm epigenetic alterations across generations in mice exposed to long-term psychological stress. It also describes incomplete DNA-methylation erasure as a route to inheritance. The cited paper does not support the additional RNA-mediated signaling mechanism or establish that the two mechanisms act in combination for trauma-related effects. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Accumulating evidence suggests that epigenetic reprogramming is not absolute.

    “However, accumulating evidence suggests that epigenetic reprogramming is not absolute.”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [139]

  • Certain genomic regions, including imprinted loci, non-imprinted loci, and retrotransposable elements, may partially escape complete demethylation.

    “Certain genomic regions, including imprinted loci, non-imprinted loci, and retrotransposable elements, may partially escape complete demethylation (139, 140).”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [139]

  • Experimental studies demonstrate that sperm-derived small noncoding RNAs, including miRNAs, tsRNAs, and lncRNA, can transmit information about paternal stress exposure independently of stable DNA methylation changes.

    “In addition, experimental studies demonstrate that sperm-derived small noncoding RNAs, including miRNAs, tsRNAs, and lncRNA, can transmit information about paternal stress exposure independently of stable DNA methylation changes (139, 140).”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [139]

    The Introduction mentions a mouse study linking paternal psychological stress to sperm epigenetic alterations, but it does not identify small noncoding RNAs as the means of transmission. The Results and discussion focus on sperm DNA methylation. Searches for miRNAs, tsRNAs, lncRNA, and transmission independent of stable DNA methylation found no passage addressing that mechanism. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Braz, C. U., Passamonti, M. M., & Khatib, H.
Affiliations
  • University of Illinois Urbana-Champaign (US)
  • Università Cattolica del Sacro Cuore (IT)
  • University of Wisconsin–Madison (US)
Corresponding author
Khatib, Hasan
ORCID
Venue
Environmental Epigenetics
Publisher
Oxford University Press (OUP)
Published
2023-12-20
Volume
10
Issue
1
Pages
dvad010-dvad010
ISSN
  • 1674-5507 (ISSN-L)
  • 2058-5888
DOI
10.1093/eep/dvad010
PMC
PMC10944287
OpenAlex
W4390024874
Cited by
19
References
4
Citations by year
2026: 7 · 2025: 10 · 2024: 2
FWCI
1.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Zoology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
USDA Agriculture and Food Research Initiative Competitive Grants (2020-67015-30828 and 2022- 07855)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
Keywords
epigenetic reprogramming, transgenerational epigenetic inheritance, DNA methylation, differentially methylated cytosines, paternal diet, methionine supplementation, transposable elements, genomic imprinting, primordial germ cells, preimplantation embryo, sheep, neural development, brain disorders, male infertility, environmental epigenetics

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