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DNA is transcribed into messenger RNA (mRNA) inside the nucleus of the cell. mRNA is a sequence of codons, which consist of 3 base pairs each. It is transported from the nucleus to the cytoplasm where it may undergo translation into a protein by way of a ribosome. Most codons represent a specific amino acid, but they may also serve as stop signals.

The ribosome reads the codons off of the mRNA and translates that information into a sequence of amino acids. In order to know which amino acid to use for each codon, it uses another kind of RNA, the transfer RNA (tRNA). Each tRNA contains an anticodon and a covalently linked amino acid. This anticodon is the complement of the codon that codes for that specific amino acid, and it is used to recognize the codon and match it to the correct amino acid. Once the ribosome finds a matching tRNA, it takes its amino acid and adds it to the protein.

You can see a picture of this process here:

https://upload.wikimedia.org/wikipedia/commons/0/0f/Peptide_...

Why did I explain all this? Because in the first article, the following is said:

> we confirm and extend prior observations that sperm undergo a dramatic switch in the RNA payload from piRNAs to tRNA fragments (tRFs) upon exiting the testis and entering the epididymis.

So, as sperm passes through the epididymis, it loses these piRNAs and gains tRNA fragments. What are these tRNA fragments? They seem¹ to be incorrectly synthesized tRNA. The tRNAs don't just appear out of nowhere, they're synthesized in the nucleus, just like mRNA. Before they're ready to be used for translation, they must undergo various processes such as aminoacylation. It seems faulty (incorrectly folded?) pre-tRNA molecules are identified and cut up into these tRNA fragments.

The authors of the article have found that this process occurs frequently in the epididymis and that the tRNA fragments are exported to the spermatozoa through vesicles:

> We found that tRNA cleavage occurs robustly in the epididymis and that small vesicles secreted by the epididymal epithelium, known as epididymosomes, carry a very similar population of small RNAs to that gained by sperm during epididymal transit

The epididymis sends tRNA fragments to sperm cells. So what? That's where the second article comes in: the authors compared the development of embryos fertilized by both pre-epididymis and post-epididymis sperm. They found that the pre-epididymis embryos expressed too many regulatory factors during development and were not able to successfully develop.

> We find that caput-derived embryos significantly overexpress ∼50 genes primarily encoding regulatory factors (RNA binding proteins and chromatin-associated factors)

If they overexpressed regulatory factors and failed to develop, it can be inferred that they underexpressed the actual genes and proteins required for development. This apparently causes what they describe as "pleiotropic defects in implantation and post-implantation development".

Meanwhile, the post-epididymis embryos were able to develop normally. It can be inferred that these normal embryos did not express as many regulatory factors, and that the tRNA fragments gained in the epididymis suppressed the expression of such factors.

It is already known in medicine that embryo-associated risk factors for abortion will probably lead to abortion within the first couple of weeks. This seems to be what's happening here: an epigenetic factor intrinsic to the embryo prevented its development past a certain early point. In this case, the female will likely not even know she was pregnant. This seems to be a rather common occurrence. Nevertheless, it's still quite interesting to figure out exactly why this happens.

Since the sperm of all males must pass through the epididymis, this seems to be most relevant for the science assisted reproduction and the procedures involved. It is my understanding that this knowledge can help decide the precise location in the genitourinary tract from which to surgically extract a male's sperm. Also, injection of the epididymal small RNAs into the embryos is apparently sufficient to rescue it from abortion, so this research might form the basis of a prophylactic procedure.

¹ https://www.ncbi.nlm.nih.gov/pubmed/21976287

3 comments

What you are calling "epigenetic factors" have been known as regulatory molecules since the origins of biology.

Epigenetics refers to the theory that some of a parent organism's phenotypes arise as a consequence of its environment/experiences and those traits can be passed on to its offspring without alterations to the gamete's DNA sequence.

With that in mind, how does any of this relates to epigenetics? Everything described here fits under the umbrella of 'basic regulatory milieu' required for sperm maturation, so it can fertilize an egg and commence embryonic development. The Smithsonian article is trying to spin this as something it's not...

"It turns out that sperm small RNAs undergo post-testes turnover, picking up intel on the father’s physical health (or lack thereof) after they’re manufactured, but before they exit the body."

It seems like they are trying to sell a classical misconception. They might as well have said: along the way the sperm picks up epigenetic information by absorbing its fathers tRNA, which pass on a variety of information about the father's life experiences, like that he was a body-builder, but also an alcoholic; and so this offspring will likely develop into that sort of person.

> how does any of this relates to epigenetics?

Epigenetics is the study of changes in organisms caused by modification of gene expression. If these articles are to be believed, then these tRNA fragments positively influence the expression of regulatory factors. It seems like an example of epigenetics to me.

> It seems like they are trying to sell a classical misconception.

I don't disagree with this assessment. The study I cited¹ said something about tRNA fragments being a conserved response to oxidative stress. The news article apparently takes this and somehow turns it into a "your children will feel the consequences of your bad dietary habits" argument.

There is some discussion and references about diets and epigenetics in the scientific text but that's not what the article is about. The articles say (1) the epididymis sends some RNA to the sperm cells, and (2) that the lack of this RNA can compromise embryo viability. It's interesting and all, but the clinical relevance of this information has yet to be determined: I'm not aware of any evidence that supports the notion that bad lifestyle habits will affect this sperm maturation process in any way.

¹ https://www.ncbi.nlm.nih.gov/pubmed/21976287

> Accumulation of RNAs of 30–35 nucleotides that correspond to tRNA halves were first reported in Tetrahymena thermophila, and subsequently shown to be a conserved response to oxidative stress in a wide variety of eukaryotes.²

² https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2553748/

This definition you provide...

Epigenetics is the study of changes in organisms caused by modification of gene expression.

...is not sufficient. The crux of epigenetics is that it involves >heritable< changes in gene expression.

At least that's what it originally meant. Now I feel like the definition is transforming into the definition you gave. However the author of the smithsonian article is confusing the two usages, because in several places the article alludes to the heritability.

Thanks for the informative and clear explanation!

Thanks.

"Also, injection of the epididymal small RNAs into the embryos is apparently sufficient to rescue it from abortion"

From my point of view at least, this is still "genetics": tomato, tomatho, RNA, DNA. RNA has just one "building block" (and there are many of the same in each) different than DNA: no thymine but uracil. Because something is in RNA and not in DNA it's not by magic "not genetic." It's all the part of the same complex mechanism of carrying the genetic information using some complex molecules, all based on the same principle. It's just that the mechanism is more complex than some obviously unsubstantiated simplification.

Whoever ever tried to see how it actually looks like knows how complex that is:

https://youtu.be/DfB8vQokr0Q?t=193

The "life" building blocks are mind-bogglingly complex to whoever expects something where 3D forms and small differences and immense parallelization don't work at the same time in astounding number of instances (e.g. a single human body has some 37 trillion of cells.. all made from a single one!).

Moreover without the different "gene expression" mechanisms doing their job there would never be any multi-cellular life, there would be neither me nor you: every multi cellular being starts from only one instance of the "program" yet the cells develop with different functions in every multi cellular body (and all these cells still contain the same program, until some mutation happens in some of them). So there is a fundamental mechanism that allows for the same "program" to behave differently a the different moments and with the different environment, even when the "environment" means the "different neighbor cells." Not to mention that what starts the new being is never just the lone DNA (which would simply not survive alone) but the fertilized cell containing all the mechanisms around that DNA (including RNA and a lot of other stuff... the whole "factories," "supply roads," "transport vehicles", "power centrals" etc, to use the equivalent words we are familiar with. A lot of these mechanisms are provided by the mother, but why should we be surprised that some are from the father too, carried with the sperm cell? We see them there. These mechanisms are all the part of the process, it's nothing "more" than it is, and it was there since the life as we know it exists.

And the (from my understanding still misleading) title about which I asked was that claim that somehow something was "passed on" that is "more than genetics".

In short, it appears to me to be an example of

https://en.wikipedia.org/wiki/No_true_Scotsman

"No true Scotsman fallacy" when somebody redefines some term "by changing the definition in an ad hoc fashion to exclude" what he wants to present as an "counterexample."