I'm very interested in understanding what non-genetic heterogeneity is and what the main causes that trigger it are. I know there are a lot of studies on this phenomenon in bacterial clonal populations, where it has been named BACTERIAL PERSISTENCE (studies by Bigger, Balaban and so on...) because these bacteria, called PERSISTERS, are able to avoid death in consequence of treatment with antibiotics. It was proposed that this behavior is due to one of these things:
1. persisters have a mutation in programmed cell death genes (bacteria aren't able to start PCD after antibiotic treatment);
2. persisters are in a "protected" stage of cell cycle that makes them able to "circumvent" antibiotics treatments;
3. persister are in a DORMANT state that makes them insensitive to the treatment in that moment.
However, the difference between PERSISTENCE and RESISTANCE is that the first is not genetically inherited but is a temporary condition of a little pool of bacteria that, once regrown after treatment, still remains sensitive to it; the second, instead, is genetically transmitted to offspring, becoming a genetic feature.
Based on what has just been said, could we use the same reasonings with eukaryotic cells? What are the causes of non-genetic heterogeneity in multicellular organisms?
Are there links between non-genetic heterogeneity and embryonic development or cancer? What is the evolutionary meanings of this phenomenon?
The paper Karima refers to provides part of the answers. However, I think the question is much wider than this paper goes. The discussion on multipotency and the occurrence of two distinct progeny has been discussed recently in another thread. Here, I believe we deal with entire organisms rather than cells. Imprinting is a good example of non-genetic modification. We all know of animal experiments that distinguish inherited behavior from imprinted behavior. Most likely the molecular mechanism behind this is "epigenetics", but there is little we know about this really. What we do know today is that next to DNA methylation, we have histone modifications and variations in microRNAs who can make a difference without having to involve any DNA mutations. Curious what others have to say on the subject!
Thanks you both for the answers.
In your mind, what are the sources of this non-genetic heterogeneity? Is it only due to epigenetics (even if the article above emphasizes that they are two different phenomena) or are there other mechanisms underlying of it?
More, since Brock et al. hypothesized that non-genetic heterogeneity could lay the groundwork for the creation of an "environment" conducive to the development of genetic mutations that lead to cancer cells development, how can a drug or a mix of drugs be effective on the multi-stable states scenario caused by this phenomenon?
Dear Maria, what do you mean by non-genetic heterogeneity? Every multicellular organism consists of numerous different cell types with different capabilities, but all cells contain the same genes. Genes do not define the phenotype of a multicellular organism, they just code for building blocks. The phenotype depends on how these building blocks are put together and for that you need a blueprint. The blueprint of multicellular organisms has not been found yet, and some argue it might be encoded in the repetitive sequences of junk DNA.
Cancer has been described as wounds that do not heal [Dvorak HF 1986]. Others have speculated that cancer represents the continuous and unregulated state of tissue repair [Beachy PA 2004]. Tumors are not just a bunch of cells that are on a "survival of the fittest" trip. Adult stem cells replenish all human tissues, they travel around and start multiplying when needed...and more importantly, they stop dividing, when tissue repair has been completed. This negative feedback does not work on malignant stem cells, because their descendants (=progenitor cells) cannot fully differentiate, and tissue repair cannot be completed; consequently the cancer stem cells remain in a proliferative state. Every cancer in every patient contains completely different mutations. Yet, the pathologist looking into a microscope can easily identify a metastasis of a breast cancer in the liver. So, despite numerous mutations the breast cancer cells usually try to resemble breast tissue...even in the liver. In this case, I would call it non-genetic similarity. ;-)
Thank you Dr. Stindl for the answer! my questions arose after the reading of the article above (posted by Dr. Al-Sahili). This article talks about non-genetic heterogeneity in a clonal population of cells. One of the first explanation this article gives us is the definition of "clonal population of cells", because it is not a trivial argument. Obviously this definition is different if you are talking about bacteria/unicellular eukaryotes or if you are talking about pluricellular eukaryotes (thus mammalian). In this latter case, all you said in your comment is true!!! We can say out loud that a human being is a clone of cells all derived from a single cell (the zygote) and we also can say that the complexity of our organism, as well as that of other higher organisms, is mostly due to the "sophistication" of the genetic program inside our cells than to the number of genes (C. elegans has got about 19.000 genes and H. sapiens about 30.000... but we look so different from worms despite we have not even twice as many their genes). The greater is the complexity of an organism the more "refined" is the genetic program inside the cells.
So, laid this foundations, the authors of the article above explicit that when they refer to a "clonal population of cells" in mammalian they mean an ensemble of cells that belong to the same tissue, have the same function and experiment the same environmental conditions (for example the same amount of morphogen during embryonic development). In spite of everything, it has been noticed that cells belong to clonal population (in the meaning just explained) can behave in different ways to the same external conditions. They bring as example the strange behaviour of a group of erythroid progenitor cells. Since they are stem cells, they express on their surface c-Kit, a stemness marker. After EPO treatment the total amount of c-Kit decreases (Western blot analysis); as a result of flow cytometry analysis they notice that the major part of cells behave as expected (decreasing their levels of c-Kit) but a small amount of cells behave INCREASING their amount of c-Kit (obviously the total amount decrease, as Western blot showed). For this reason they subdivide the initial clonal population of cells into two subpopulations (High c-Kit subpopulation and Low c-Kit subpopulation). They are't able to give us an explanation of this strange behaviour. Why that ensemble of clonal cells shows these two different phenotypic behaviours as answer to the SAME amount of EPO? And moreover... my question is... is this strange behaviour due to particular inner (thus genetic) conditions of each cell or is it due to a not yet explainable causes that are not depending on genes? The authors of the article affirm that non-genetic heterogeneity exists, and both the example above and the well-studied bacterial persistance are two example of it.
Another article talks about the role of non-genetic heterogeneity in cancer [Brock et al., 2009]. It’s widely and commonly widespread the idea that cancer arises due to multiple DNA modifications that cause the deregulation of pivotal pathways inside the cell. Let's imagine this scenario: an homogeneous population of cell with rare drug-resistant mutant . Once cytotoxic drugs treatment starts, classical selection of rare cells with a pre-existing genetic mutation that confers resistance to drugs acts, causing the death of wild-type cells but not of the drug resistant cells. This permits the expansion of cancer resistant mutants. Now let's imagine another scenario: in the non-genetic heterogeneity view the components of a wild-type homogeneous clonal population could be subdivided in phenotypically resistant fraction and phenotypically not resistant fraction. The exposure of this heterogeneous population to cytotoxic drugs could cause the survival only of phenotypically resistant wild-type cells. The transient amplification of these variants increases the chance of acquiring genetic restistance-conferring mutations that allow them to be resistant to a second wave of treatment. (It is important to note that this hypothesis doesn’t imply that genetic mutations are not necessary but, rather, that it confers an evolution advantage in the Darwinian selection. On this point we can conclude that genetic and non-genetic variation may not act independently)
Why this behaviour?
What is actually this non-genetic heterogeneity and by what criteria does it work?
What is your opinion about this?
The article above specifies that non-genetic heterogeneity differs from epigenetics. Why???
Does this non-genetic variability underneath actually exist or not?
Could we give any "genetic" explanations?
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