Studies question how epigenetic information is inherited

It’s not as pervasive as was previously thought.

Agouti mice. Credit: Randy Jirtle and Dana Dolinoy
Agouti mice. Credit: Randy Jirtle and Dana Dolinoy

Many studies in recent years have suggested that our eating regimen, our habits or traumatic experiences can have ramifications for the health of our kids – and even our grandkids.

The clarification that has increased most money for how this happens is supposed ‘epigenetic inheritance’ – patterns of chemical ‘marks’ close by our DNA that are hypothesized to be passed down the generations.

A new study by the University of Cambridge suggests that one way that environmental effects are passed on may, in fact, be through molecules produced from the DNA known as RNA that is found in a father’s sperm.

The mechanism by which we acquire intrinsic attributes from our parents is well known: we acquire half of our genes from our mom and a half from our dad. In any case, the mechanism whereby a ‘memory’ of the parent’s environment and conduct may be gone down through the ages isn’t comprehended.

Epigenetic inheritance has demonstrated convincing and popular clarification. The human genome is comprised of DNA – our genetic blueprint. Be that as it may, our genome is supplemented by various ‘epigenomes’ that differ by cell type and developmental time point.

Epigenetic marks are connected to our DNA and direct to some degree whether a quality is on or off, impacting the function of the gene. The best comprehended epigenetic adjustment is DNA methylation, which puts a methyl group on one of the bases of DNA.

One model in which DNA methylation is related with epigenetic inheritance is a mouse freak called Agouti Viable Yellow. The coat of this mouse can be totally yellow, totally brown, or an example of these two colors– yet, surprisingly, in spite of their diverse coat colors, the mice are hereditarily indistinguishable.

The clarification of how this happens lies with epigenetics. Beside one of the key genes for coat color lies a segment of hereditary code known as a ‘transposable element’ – a small portable DNA ‘cassette’ that is really repeated ordinarily in the mouse genome however here acts to manage the coat color gene.

In the case of the gene for coat color, if methylation switches off the transposable element completely, the mouse will be brown; if an acquisition of methylation fails completely, the mouse will be yellow. But this does not affect the genetic code itself, just the epigenetic landscape of that DNA segment.

But then, a yellow-coated female will probably have yellow-coated posterity and a brown-coated female will probably have brown-coated posterity. At the end of the day, the epigenetically managed conduct of the transposable component is some way or another being acquired from parent to posterity.

A group driven by Professor Anne Ferguson-Smith at Cambridge’s Department of Genetics set out to look at this wonder in more detail, asking whether comparable variably-methylated transposable elements existed somewhere else that could impact a mouse’s qualities, and whether the ‘memory’ of these methylation examples could be passed starting with one generation then onto the next.

Scientists found that while these transposable elements were common throughout the genome – transposable elements comprise around 40% of a mouse’s total genome – the vast majority were completely silenced by methylation and hence had no influence on genes.

Only around one in a hundred of these sequences were variably-methylated. Some of these are able to regulate nearby genes, whereas others may have the ability to regulate genes located further away in the genome in a long-range capacity.

When scientists observed the extent to which the methylation patterns on these regions could be passed down to subsequent generations, only one of the six regions they studied in detail showed evidence of epigenetic inheritance – and even then, the effect size was small. Furthermore, only methylation patterns from the mother, not the father, were passed on.

Tessa Bertozzi, a Ph.D. candidate and one of the study’s first authors said, “One might have assumed that all the variably-methylated elements we identified would show memory of parental epigenetic state, as is observed for coat color in Agouti Viable Yellow mice. There’s been a lot of excitement and hype surrounding the extent to which our epigenetic information is passed on to subsequent generations, but our work suggests that it’s not as pervasive as was previously thought.”

“In fact, what we showed was that methylation marks at these transposable elements are reprogrammed from one generation to the next. There’s a mechanism that removes methylation from the vast majority of the genome and puts it back on again, once in the process of generating eggs and sperms and again before the fertilized egg implants into the uterus. How the methylation patterns at the regions we have identified get reconstructed after this genome-wide erasure is still somewhat of a mystery.”

“We know there are some genes – imprinted genes for example– that do not get reprogrammed in this way in the early embryo. But these are exceptions, not the rule.”

Professor Ferguson-Smith says that there is evidence that some environmentally-induced information can somehow be passed down generations. For example, her studies in mice show that the offspring of a mother who is undernourished during pregnancy are at increased risk of type 2 diabetes and obesity – and their offspring will, in turn, go on to be obese and diabetic. Again, she showed that DNA methylation was not the culprit – so how does this occur?

The appropriate response may originate from research at the Wellcome/Cancer Research UK Gurdon Institute, additionally at the University of Cambridge, in a joint effort with the lab of Professor Isabelle Mansuy from the University of Zürich and Swiss Federal Institute of Technology. In an examination did in mice, they report how the ‘memory’ of early life trauma can be passed down to the next generation through RNA particles conveyed by sperm.

Dr Katharina Gapp from the Gurdon Institute and the Mansuy lab have already demonstrated that injury in postnatal life increases the risk of social and metabolic disorders in the straightforwardly uncovered people as well as in their subsequent offspring.

Now, scientists have shown that the trauma can cause alterations in ‘long RNA’ (RNA molecules containing more than 200 nucleotides) in the father’s sperm and that these contribute to the inter-generational effect. This complements earlier research that found alterations in ‘short RNA’ molecules (with fewer than 200 nucleotides) in the sperm. RNA is a molecule that serves a number of functions, including, for some of the long versions called messenger RNA, ‘translating’ DNA code into functional proteins and regulating functions within cells.

Using a set of behavioral tests, the team showed that specific effects on the resulting offspring mediated by long RNA included risk-taking, increased insulin sensitivity, and overeating, whereas small RNA conveyed the depressive-like behavior of despair.

Dr. Gapp said: “While other research groups have recently shown that small RNAs contribute to an inheritance of the effects of chronic stress or changes in nutrition, our study indicates that long RNA can also contribute to transmitting some of the effects of early life trauma. We have added another piece to the puzzle for potential interventions in the transfer of information down the generations.”

References:

  • Kazachenka, A, Bertozzi, TM et al. Identification, Characterization, and Heritability of Murine Metastable Epialleles: Implications for Non-genetic Inheritance. Cell; 25 Oct 2018; DOI: 10.1016/j.cell.2018.09.043
  • Gapp K et al. Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma. Molecular Psychiatry; 30 Oct 2018; DOI: 10.1038/s41380-018-0271-6