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Monday Article #77: Epigenetic Inheritance: Myth or Reality

Can we inherit acquired traits? If we exercise, do our offsprings automatically become fitter? Classical Mendelian inheritance tells us no. There’s a but though……

Heredity is overwhelmingly acknowledged to be governed by the laws of Gregor Mendel, where genes act as the primary templates of inherited information. However, recent progressions in biology have highlighted exceptions to these rules, suggesting that genes may only be part of the picture. One of these exceptions is epigenetic inheritance.

Epigenetics is defined as the alterations in the genes expressed in a cell that are not caused by changes in the DNA sequence (Peschansky and Wahlestedt, 2013). Epigenetic inheritance therefore refers to the transmission of these non-DNA sequence modifications to offspring.

In mammals, reprogramming of the cell’s epigenetic states occurs twice, once post-fertilization, and once when giving rise to early gametes (Xia and Xie, 2020). These two rounds of erasures ensure that the probability of inheritance of epigenetic marks is low, though not impossible as some regions of the gametes are resistant to reprogramming (Brykczynska et al., 2010).

Figure 1: Life cycle of mammalian organisms with labeled de-methylation and methylation processes. Image taken from Epigenetic Inheritance: Concepts, Mechanisms and Perspectives (Lacal and Ventura, 2018).

Evidence of epigenetic inheritance in animals

Since it is widely accepted that transgenerational epigenetic inheritance occurs in plants regularly due to their lower reliance on epigenetic reprogramming in their gametes, we will primarily discuss evidence supporting the existence of epigenetic inheritance in animals.

To discuss all evidence regarding epigenetic inheritance in animals would far exceed the scope of this article, so below I will only be discussing some prominent ones.

Perhaps one of the earlier studies to document epigenetic inheritance across multiple generations is examining coat color. Understanding the study requires a bit of molecular biology background. In the mice that were bred, transcription of an intracisternal A particle (IAP) retrotransposon causes ectopic expression of the agouti (A) gene that results in yellow fur, obesity, diabetes, and increased susceptibility to tumors. The degree of methylation of the IAP is inversely correlated with the degree of transcription of it. Furthermore, the phenotype of the offspring is related to the phenotype of the mother and persists across multiple generations. This epigenetic inheritance results from the resistance of IAPs to epigenetic inheritance especially in the female germline, and maternal genome post-fertilization (Morgan et al., 1999). 

Figure 2: Pedigree tree of inheritance of yellow coat. Circle represents female while square represents male. Image taken from Epigenetic inheritance at the agouti locus in the mouse (Morgan et al., 1999).

A low-protein diet over 10 generations produces even more severe cognitive deficits, which are evident after two generations, even after returning to a regular diet (Stewart et al., 1980). A maternal high-fat diet in mice also increases body size and insulin sensitivity, which endured till the second generation, though it nearly vanished in the F3 generation (Dunn and Bale, 2009). The persistence through the F2 (grandchild) and F3 (great-grandchild) generation is important when discussing epigenetic inheritance where the father or mother is affected respectively as maternal exposure can affect down to the germline of the developing embryo (the conditions of a mother’s womb can affect the cells of a grandchild), whereas paternal exposure can only affect the germline of the F1 generation (Lim and Brunet, 2013). Another study showed that the administration of corticosterone to male mice for two months before mating caused a depressive-like phenotype in male F2 offspring (Short et al., 2016).

Figure 3: Framework for determining the existence of transgenerational epigenetic inheritance. Image taken from Bridging the transgenerational gap with epigenetic memory (Lim and Brunet, 2013).

Aside from negative environments, male mice (F0) that have been exposed to environmental enrichment gave rise to a positive effect on stress responsivity in the F2 generation (Yeshurun et al., 2017). 

In humans, male children who were exposed to intrauterine undernourishment during the 5-month Dutch famine as well as their offspring developed obesity, glucose intolerance, and coronary heart disease in adult life (Painter et al., 2008, Lumey, Stein and Susser, 2011, Veenendaal et al., 2013). These symptoms were associated with altered levels of DNA methylation 60 years later (Heijmans et al., 2008). A Norwegian longitudinal study on Vietnamese refugees also reported a high risk of mental disease in F3 offspring when grandparents were diagnosed with post-traumatic stress disorder on their arrival in Norway (Vaage et al., 2011). The Överkalix cohort study has reported the effects of ample or poor food availability to Norwegian children and adolescents on the longevity of their descendants showing a risk of death due to diabetes and increased lifespan in grandchildren, respectively (Kaati, Bygren and Edvinsson, 2002, Bygren, Kaati and Edvinsson, 2001). Another study has also shown that methylation in the pro-opiomelanocortin (POMC) gene, that increases risk of obesity, is highly correlated with paternal somatic methylation (Kühnen et al., 2016). Human studies however are much less controlled for environmental and cultural confounders.

There has also been evidence against epigenetic inheritance. One group of researchers showed that inherited phenotypes due to hormonal disruption of gene expression were inherited only in one generation (Iqbal et al., 2015). One main problem with the study though is that the researchers did not assess phenotypic changes but only assumed molecular changes to reflect phenotype. Their failure to detect molecular changes in DNA methylation after the second generation was assumed to contradict previous research. Epigenetic inheritance however involves two independent steps, initiation which involves molecular changes, and propagation which translates the molecular changes to inheritable secondary features. Here, some initial methylation changes may be replaced with other modifications (Gapp et al., 2014). Hence, it is possible that the initial molecular changes in the first generation were translated into epigenetically inherited marks that were not measured. Indeed many other studies showed that parent (F0) mice exposed to an endocrine disruptor used in the negative study showed increased sensitivity to stress (Crews et al., 2012), changes in germ cells (Skinner et al., 2013), and diseases of the reproductive organs persisting through to the F3 generation (Manikkam et al., 2012). Furthermore, epigenetic inheritance may not only act through DNA methylation as discussed below.

Mechanisms of epigenetic inheritance

There are plenty of proposed mechanisms of epigenetic inheritance, but some are more dominant than others, which we will discuss.

Among mechanisms, methylation is the most well-understood mechanism for epigenetic inheritance. DNA methylation is an enzymatic process by which a methyl group (CH3) is bound to a cytosine residue. This methylation may repress or increase transcriptional activity depending on the location (Jones, 2012). Methylation is catalyzed by DNA methyltransferases (DNMTs) (Chen and Li, 2004). Methylation patterns can be erased by two mechanisms: active and passive demethylation. Passive demethylation results from failure in maintenance during the replication of DNA, primarily in the absence of functional DNMT1 (Wu and Zhang, 2014). Active demethylation is mediated by ten-eleven translocation (TET) proteins. Without going too deep, TET catalyzes the oxidation of the modified cytosine residue into another form, where it is excised from DNA. The resulting gap is then repaired, generating an unmodified cytosine. The intermediates are also less effective substrates of DNMT1 which fosters passive demethylation (Zhao and Chen, 2013). Epigenetic transmission might be possible when a step in demethylation is prevented, as in the case of genomic imprinting, which constitutes the strongest evidence for transgenerational epigenetic inheritance in mammals (van Otterdijk and Michels, 2016). This can happen due to specific factors such as Stella that prevent demethylation by binding H3K9me2 and blocking TET3 activity at the maternal genome (M. Jorge Cardoso and Leonhardt, 1999). 

Figure 4: How DMNT and TET facilitate methylation and demethylation of cytosine residues. Image taken from Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (Wu and Zhang, 2014).

More recently, non-coding RNA (ncRNA) have been implicated in epigenetic inheritance. Long non-coding RNA (lncRNA) can regulate epigenetics by remodeling chromatin structure, whereas miRNAs, another form of ncRNA modify epigenetics by regulating directly and indirectly DMNT expression (Peschansky and Wahlestedt, 2013). Notably, miRNA controls de novo DNA methylation (methylation after phases of reprogramming) by regulating transcriptional repressors (Sinkkonen et al., 2008). In fact, the injection of specific miRNAs into fertilized eggs in mice results in transgenerational inheritance of cardiac hypertrophy and large body size (Wagner et al., 2008).

Concluding remarks

As of today, I’m fairly confident that epigenetic inheritance intergenerationally (across one generation only), or transgenerationally (across multiple generations) occurs in all organisms and non-human animals respectively. However, how much of it is due to the environment, and the extent to which transgenerational epigenetic inheritance happens in humans remain unclear. Our best bet at proving its occurrence in humans might be analyzing future generations of those experiencing the Dutch famine to see if their epigenetic changes persist.


Article prepared by: Jared Ong Kang Jie, R&D Director of MBIOS 2023/2024

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