The stream of time sweeps away errors, and leaves the truth for the inheritance of humanity.

—Georg Brandes

Approximately 10% of the protein pool encoded by the mammalian genome plays a role in transcription or chromatin regulation.  Given that the mammalian genome consists of 3,000,000,000 base pairs this gives rise to an astounding array of possible regulatory messages, including DNA binding interactions, histone modifications, histone variants, nucleosome remodeling, DNA methylation and non-coding RNA.

The maintenance of a repressed or activated status of a gene is often necessary for cellular differentiation.  This observation should not be very surprising: A person’s liver cells, skin cells and kidney cells look different and behave quite differently, yet the all contain the same genetic information. With very few exceptions the differences between specialized cells are epigenetic (e.g. “post-genomic” or “post-translational”), not genetic.  The remarkable thing about specialized cells is that not only can they acquire specialized traits and functions through development; they can also pass on these phenotypic manifestations to their own daughter cells. Although their DNA sequences remain unchanged during development, differentiated cells nevertheless acquire information that they pass on to their succeeding generations. The transmission of this sort of information is known as epigenetic inheritance systems (EIS).

Although histone modifications have been predicted to affect transcription almost since their discovery in the mid 1960’s  the existence of epigenetic inheritance was not widely recognized until the mid 1970’s. Embryologists had always wrestled with the basis for cell differentiation, but were more interested in the signaling that switched genes on and off and the cascade of events that lead cells to become specialized. Less research interest was placed on how cells seem to remember this new state and how they passed it off to their progeny. In 1975, a series of articles independently suggested a mechanism that would enable states of gene activity and inactivity to be maintained and transmitted to future cell generations.

The Types of Epigenetic Inheritance Systems:

1. Self-sustaining loops
2. Architectural changes
3. Chromatin marking systems

The most elemental form of EIS is known as the self-sustaining loop, first described theoretically by the American geneticist Sewall Wright in 1945. The essence of self-sustaining loop is that X causes Y, and Y causes X. An example might be a temporary environmental cue that turns a gene on and the product of that gene in turn ensures the continued activity of the gene. In this case the product of gene A is gene A’s own regulator, attaching to the control region of A and keeping it active long after the environmental cure that induced it has dropped out and disappeared. Following cell division, the level of protein A is high enough in the daughter cells to induce further activity from their own genes. You might recognize that there is significant potential for phenotypic variation here; since protein production is itself subject to stochastic variation, it is quite possible that two daughter cells could have differing amounts of protein A and perhaps in one the level is below the amount needed to activate the gene A regulator. In this daughter cell, the gene might then deactivate, producing two daughter cells with quite different phenotypes. In a self-sustaining loop, the functional state is dependant on the interactions between the constituent elements. The state of the loop is transmitted from generation to generation as a whole, and it varies as a whole. The nondecomposable nature of the information in this type of system is called holistic and it is very different from decomposable systems, like DNA where the components (nucleotides) can be changed without destroying the whole system.

The second type of epigenetic inheritance involves architectural changes to the cell structure and the subsequent transmission of these structural changes to the offspring. The British biologist Thomas Cavalier-Smith has advanced the basis for this form of inheritance.  Cell membranes, such as the plasma membrane that surrounds the cell or the internal membrane system of the endoplasmic reticulum differ from each other in both composition and location. They cannot assemble without guidance, and their consistency and continuity depend on preexisting membranes, which act as templates for more membranes with the same structure. From this templating, the membrane grows and eventually divides between daughter cells. Cavalier-Smith refers to as the membranome, and believes that many of the most important landmark events in early development, including the formation of the first cell were dependent on changes to the membranome.

There appears to be some evidence for this mechanism in the unique patterns of inheritance seen in the prion diseases, such as Creutzfeldt-Jakob disease and kuru. A prion is an infectious agent that is composed primarily of protein. To date, all such agents have been discovered to propagate by transmitting a misfolded protein state. As with viruses the protein itself does not self-replicate, rather it induces existing polypeptides in the host organism to take on the rogue form. Prion particles can be transferred from one cell generation to the next and in each instance modify normal proteins to assume prion-like characteristics. Certain sea slugs use a prion-like protein to remember certain experiences; and undoubtedly, more prion-like mechanisms will be identified in the future.

The third system of epigenetic inheritance is known as the chromatin marking systems. Chromatin is the stuff of chromosomes. It is the DNA plus all the RNA, proteins and whatever other molecules happen to be associated with it. We’re interested in the non-DNA features of chromatin, as these are the aspects of chromatin transmitted generation to generation that enable states of gene activity to be perpetuated in the cell lineages.

Chromatin Marking Systems:

1. DNA methylation and demethylation
2. Histone methylation and demethylation
3. Histone acetylation and de-acetylation
4. Phosphorylation
5. Ubiquitination, deubiquitination, and SUMOylation
6. RNA interference (secondary)

REFERENCES

1. Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389 (6648): 251–60. 1997
2. Kupiec JJ. The Origin of Individuals. World Scientific Press Singapore (2009)
3. Ibid 2.
4. Allfrey VG, Faulkner R, Mirsky AE. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc. Natl. Acad. Sci. U.S.A. 51:1964
5. Felsenfeld G, Groudine M. Controlling the double helix. Nature 421 (6921): 448–53. 2003
6. Jablonka E and Lamb M. Evolution in Four Dimensions. The MIT Press. Cambridge MA 2006
7. Holliday R, Pugh JE. DNA modification mechanisms and gene activity during development. Science. 1975 Jan 24; 187(4173):226-32.
8. Riggs AD. X inactivation, differentiation, and DNA methylation. Cytogenet Cell Genet. 1975; 14(1):9-25.
9. Ibid 6.
10. Cavalier-Smith TH. “Membranome and Membrane Heredity in Development and Evolution” by in:  Organelles, Genomes, and Eukaryote Phylogeny: An Evolutionary Synthesis in the Age of Genomics. Editors: Hirt RP and Horner DS. CRC Press (2004)