Transgenerational Epigenetic Inheritance Mechanisms

Transgenerational epigenetic inheritance describes the transfer of phenotypic traits across generations via heritable changes in gene regulation rather than alterations in DNA sequence. These mechanisms encompass covalent modifications of DNA, such as cytosine methylation, post-translational marks on histone proteins that modulate chromatin accessibility, and the carriage of non-coding RNAs or proteins within gametes. Environmental factors experienced by parents—ranging from diet and pollutants to stress—can remodel germline epigenomes and persist through fertilisation and embryonic development, bypassing widespread epigenetic reprogramming. This process offers a molecular basis for how ancestral exposures influence offspring disease susceptibility, metabolic homeostasis, reproductive function and neurobehavioural phenotypes. Unravelling these pathways highlights potential interventions to mitigate inherited risks and informs our understanding of evolutionary adaptation and public health.

Research from Nature Portfolio

Recent studies have revealed that paternal diet can shape offspring metabolism through sperm-borne mitochondrial RNAs. In mouse models of acute high-fat feeding, epididymal sperm accumulate specific mitochondrial tRNAs and their fragments, which are delivered to oocytes at fertilisation and influence early embryonic transcriptional programmes governing energy balance. In humans, sperm mitochondrial tRNA fragment levels correlate with body mass index, implicating a conserved role in transgenerational metabolic regulation. Another investigation demonstrated that paternal exposure to a folate-antagonist drug alters sperm small RNA profiles and RNA methylation. Altered abundance of tRNA halves and enrichment of m5C modifications, driven by DNMT2 methyltransferase in the testis, was sufficient to induce craniofacial defects when RNA fractions were microinjected into zygotes. These findings underscore the capacity of sperm RNA cargo and modifications to mediate inherited phenotypes.

Research from all publishers

A study of paternal pre-pregnancy caffeine exposure has shown that elevated corticosterone levels induce hypermethylation of the miR-142-3p promoter in sperm, leading to persistent reduction of this microRNA in offspring. Male progeny develop non-alcoholic steatohepatitis marked by lipid dysregulation and inflammation, which can be mitigated by restoring miR-142-3p levels. In another model, paternal inhalation of fine particulate matter (PM2.5) was found to elicit male-specific primary hypogonadism across generations. Sperm small RNAs, including specific miRNAs and piRNAs, were altered and targeted key genes in testosterone synthesis. Changes in sperm RNA profiles led to hypermethylation of Leydig cell regulatory loci, impairing steroidogenesis in F1 and F2 males. These diverse environmental insults highlight non-coding RNA and DNA methylation as central mediators of transgenerational effects.

Transgenerational Epigenetic Inheritance Mechanisms publication trend

The graph below shows the total number of articles in transgenerational epigenetic inheritance mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

DNA methylation: Addition of a methyl group to cytosine bases in DNA, typically repressing gene expression.

Histone modification: Post-translational chemical changes (e.g. acetylation, methylation) to histone proteins that influence chromatin structure and transcriptional activity.

Non-coding RNA (ncRNA): RNA molecules not translated into protein, including microRNAs, tRNA fragments and piwi-interacting RNAs, which regulate gene expression.

tRNA fragment (tsRNA): Small RNAs derived from transfer RNAs that can modulate gene expression and are implicated in intergenerational signalling.

DNMT2 methyltransferase: An enzyme that methylates RNA cytosine residues, influencing RNA stability and function in germ cells.

Epididymosome: Extracellular vesicles secreted in the male reproductive tract that transfer proteins and RNAs to maturing sperm.

References

1. Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs. Nature (2024).
2. Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring. Nature Communications (2023).
3. Sperm miR‐142‐3p Reprogramming Mediates Paternal Pre‐Pregnancy Caffeine Exposure‐Induced Non‐Alcoholic Steatohepatitis in Male Offspring Rats. Advanced Science (2024).
4. Inter- and trans-generational impacts of real-world PM2.5 exposure on male-specific primary hypogonadism. Cell Discovery (2024).