Debunking myths on genetics and DNA

Friday, December 9, 2011

Understanding the cell nucleus in order to unravel the mystery of epigenetic heritability

The above image is the striking view of the surface of a cell nucleus (in pink). The dark crater represents a hole in the nucleus and offers a peek inside: the granular consistency that you see there are the chromosomes, bundled together in what may appear a random distribution but, in reality, is nothing but random:
"In all eukaryotic species analyzed so far, spatial genome arrangements are nonrandom: chromosomes or genomic loci occupy preferential positions with respect to each other and/or to nuclear landmarks [1]."
The nucleus contains a combination of DNA and proteins (mostly histones) called chromatin. Histones can be thought of spools around which the DNA wraps, forming a structure called nucleosome. Proteins in the chromatin can be silenced or activated, thus allowing differentiated cells to express only the genes necessary to their specific function. The budding yeast Saccharomyces cerevisiae was the first eukaryote cell to have its entire genome sequenced and, due to its relatively compact size (16 small chromosomes), it has been studied extensively to understand the structure of the cellular nucleus. For example, one of the largest protein complexes on the nuclear envelope is the nuclear pore complex, or NPC, which modulates the exchange of components between the nucleus and the cytoplasm. Several genes are relocated to the NPC when activated, and, as Zimmer and Fabre note [1],
"The region close to the nuclear envelope thus emerges as a mosaic, with the vicinity of NPCs representing zones favorable to transcription, whereas the zones between NPCs are more repressive."
These spatial arrangements are not static but they undergo re-arrangements (through complicated chemical alterations like cytosine methylation and/or post-translational modification of the histone amino acids). The extent of packaging of the nucleosome affects gene expression, however, to this day, little is known on what determines this delicate spatial arrangement.

And here's the intriguing bit: the re-arrangements the chromatin undergoes are generally reversible. And yet there's a level of these modifications that not only remains unmodified, it becomes inherited [2]:
"Chromatin modifications are often termed epigenetic marks; however, an unresolved issue in the field is the relationship between these modifications, including those established during transcription, and epigenetic inheritance (that is, the stability of these alterations during cell divisions and development). It seems that most, if not all, histone modifications are reversible, so it remains to be determined how epigenetic persistence of chromatin states is achieved, and which modifications are heritable."
These are the transgenerational epigenetic modifications I have discussed here and here. It's a real puzzle because heritability happens through the germ line cells, but in this cell line transcription only happens de-novo after fertilization. So at what level and how are epigenetic changes inherited? In [2], Berger reviews the various types of chromatin modifications and concludes with a nice analogy:
"Language is defined by the Webster dictionary as systematic means of communicating ideas using conventionalized signs or marks having understood meanings. This definition can be used to describe the complexity of the relationship between epigenetic marks and the biological processes they influence. As scientists, it falls to us to learn and understand this language a task that we have only begun to undertake."
EDIT: as I was preparing this post, I found this article on Scientific American, which talks about untangling the 3D human genome, and how the topology inside the nucleus determines which genes are on and off. There's a neat video, if you scroll to the bottom of the article.

[1] [1] Zimmer, C., & Fabre, E. (2011). Principles of chromosomal organization: lessons from yeast The Journal of Cell Biology, 192 (5), 723-733 DOI: 10.1083/jcb.201010058

[2] Berger, S. (2007). The complex language of chromatin regulation during transcription Nature, 447 (7143), 407-412 DOI: 10.1038/nature05915


  1. Ah Ha--Ramen noodles explains it all!

    I saw this post: Protein Folding that talks about a paper on protein folding. It seems like an interesting approach.

  2. I saw that post and to be honest I was quite surprised to see that you can do that. I always thought the sequencing data was NOT enough because there were so many other variables like temperatures and p.H. and entropy... I need to read it one more time and try to understand it better.

  3. Recently I read that epigenetic markers are erased in the fertilized egg. Some scientists however sustain that some of the marking is maintained. Can you please explain in more detail why it seems that epigenetic markers cannot be inherited and how this relates to the fact that transcription happens only de-novo after fertilization. I am not able to understand.
    Is it possible to conclude that the exact mechanism of heritable epigentic changes is not yet known? I ask because I am looking since several days for articles that might explain the mechanism. Can I just stop looking (for the time being) ?

  4. Hi Marleen, did you see this paper? My understanding is that it was originally thought that they couldn't be inherited, but recent papers have shown more and more evidence that indeed they are (see also this and this). But as far as I know the mechanism by which epigenetic markers are inherited is still unknown. If I hear otherwise I will let you know. :)

  5. PS I found a couple of more papers, I'll read them and discuss them next week! Thanks for reading, please come back for further discussions.

  6. EEGiorgi,

    Thank you so much for the links. I will certainly follow your blogs not only to read your coming posts on epigenetics but also because the others subjects you write about are very interesting as well. I am very happy of having 'discovered' about your blog.


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