pp. 5770·30. decembar 2024.· Issue No. 1
Molecular carriers of transgenerational epigenetic inheritance in mammals: a comprehensive review and the tcmsi carrier-mechanism sufficiency framework
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Rafael Souza MendesORCID 0009-0006-2630-1030
DOI: https://doi.org/10.65932/CAR-2024-1-5Creative Commons BY-NC-ND 4.0 CC BY-NC-ND 4.0
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Molecular carriers of transgenerational epigenetic inheritance in mammals: a comprehensive review and the tcmsi carrier-mechanism sufficiency framework
Transgenerational epigenetic inheritance (TGEI) in mammals — the transmission of phenotype-relevant epigenetic information from an exposed F0 generation to unexposed F3 (maternal lineage) or F2 (paternal lineage) generations through germline mechanisms — has, in the 2016-2022 window, accumulated a substantial empirical literature spanning at least five candidate molecular carrier classes: residual DNA methylation surviving the two genome-wide reprogramming events, sperm-borne transfer-RNA-derived small RNAs (tsRNAs) and their post-transcriptional modifications, sperm microRNAs (miRNAs), retained histone posttranslational modifications at sperm-resistant loci, and higher-order chromatin-architecture features including topologically associating domains and centromeric heterochromatin organisation. Each carrier class has accumulated its own evidentiary profile across detection robustness, reprogramming-bypass mechanism, zygote-rescue causality, cross-species evolutionary conservation, and therapeutic-translation actionability. The literature has, however, been organised predominantly around specific phenomenological claims — paternal-diet metabolic inheritance, paternal-stress behavioural inheritance, Holocaust FKBP5 trauma transmission, gestational-famine epigenetic imprints — rather than around the molecular carriers themselves. The companion article in this series introduced the Mammalian Transgenerational Epigenetic Inheritance Evidence Index (MTEII) to evaluate the claim-level evidentiary strength of specific TGEI cases; the present review introduces, as the complementary original contribution, the Transgenerational Carrier-Mechanism Sufficiency Index (TCMSI), a normalised composite metric — bounded on [0,1] — that integrates five carrier-mechanism dimensions (detection robustness in mammalian germline, reprogramming-bypass mechanism specificity, demonstrated zygote-rescue causality, inter-species evolutionary conservation, and therapeutictranslation actionability) and returns a quantitative ranking of the five carrier classes on a metric explicitly designed to evaluate molecular-mechanism sufficiency rather than claim-level evidentiary support. Applied to the five canonical carrier classes, TCMSI returns the highest score for sperm tsRNAs and their DNMT2-mediated modifications (≈0.62), intermediate scores for sperm miRNAs (≈0.55) and residual DNA methylation (≈0.42), and lower scores for retained histone modifications (≈0.35) and higher-order chromatin architecture (≈0.28).

Transgenerational epigenetic inheritance (TGEI) in mammals — the transmission of phenotype-relevant epigenetic information from an exposed F0 generation to unexposed F3 (maternal lineage) or F2 (paternal lineage) generations through germline mechanisms — has, in the 2016-2022 window, accumulated a substantial empirical literature spanning at least five candidate molecular carrier classes: residual DNA methylation surviving the two genome-wide reprogramming events, sperm-borne transfer-RNA-derived small RNAs (tsRNAs) and their post-transcriptional modifications, sperm microRNAs (miRNAs), retained histone posttranslational modifications at sperm-resistant loci, and higher-order chromatin-architecture features including topologically associating domains and centromeric heterochromatin organisation. Each carrier class has accumulated its own evidentiary profile across detection robustness, reprogramming-bypass mechanism, zygote-rescue causality, cross-species evolutionary conservation, and therapeutic-translation actionability. The literature has, however, been organised predominantly around specific phenomenological claims — paternal-diet metabolic inheritance, paternal-stress behavioural inheritance, Holocaust FKBP5 trauma transmission, gestational-famine epigenetic imprints — rather than around the molecular carriers themselves. The companion article in this series introduced the Mammalian Transgenerational Epigenetic Inheritance Evidence Index (MTEII) to evaluate the claim-level evidentiary strength of specific TGEI cases; the present review introduces, as the complementary original contribution, the Transgenerational Carrier-Mechanism Sufficiency Index (TCMSI), a normalised composite metric — bounded on [0,1] — that integrates five carrier-mechanism dimensions (detection robustness in mammalian germline, reprogramming-bypass mechanism specificity, demonstrated zygote-rescue causality, inter-species evolutionary conservation, and therapeutictranslation actionability) and returns a quantitative ranking of the five carrier classes on a metric explicitly designed to evaluate molecular-mechanism sufficiency rather than claim-level evidentiary support. Applied to the five canonical carrier classes, TCMSI returns the highest score for sperm tsRNAs and their DNMT2-mediated modifications (≈0.62), intermediate scores for sperm miRNAs (≈0.55) and residual DNA methylation (≈0.42), and lower scores for retained histone modifications (≈0.35) and higher-order chromatin architecture (≈0.28).

Objavljeno30. decembar 2024.
Stranice5770
AutoriRafael Souza Mendes