Mechanisms Of Epigenetic Inheritance

It may seem trivial to say that cancers are caused by genetic alterations in their constituent cells (^2.1), but it is not. Many properties of tumor cells are determined by their pattern of gene expression and do neither necessarily require structural alterations of gene products by mutations nor alterations in the structure of gene regulatory elements nor in gene dosage. Evidently, very different patterns of gene expression are established in normal cells of the human body and can in many cases be stably maintained during proliferation.

For instance, tissue stem cells retain their phenotype through several thousand divisions in a human life-time. Likewise, cell differentiation in humans is in general achieved without alterations in the sequence and amount of DNA. There are a few exceptions. Differentiation of B- and T-lymphocytes involves gene rearrangements with loss of small DNA segments from the immunoglobin and T-cell receptor genes, respectively. In some tissues, terminally differentiated cells are polyploid.

So, theoretically, a tumor cell phenotype could be achieved by mechanisms similar to those that determine normal differentiated states. In general, mechanisms leading to a stably inherited phenotype without changes in the DNA sequence and content of a cell are designated as 'epigenetic'. In reality, no malignant tumors in humans appear to be caused exclusively by epigenetic mechanisms. Instead, in most cancers, epigenetic alterations complement genetic alterations and in many, they appear to be essential.

The definition of what is considered as epigenetic has undergone fluctuations over the last decades (Table 8.1). It is generally agreed that genomic imprinting and

X-chromosome inactivation are prime examples. In both cases, identical DNA sequences are differentially expressed in a stably inherited fashion. One mechanism involved in fixing this differential expression is DNA methylation at cytosine residues, which is thus another exemplary epigenetic mechanism. DNA methylation is also instrumental in other instances of gene silencing and of facultative heterochromatin formation. Further mechanisms contribute, notably posttranslational modifications of histones, in particular methylation at specific lysine residues. In comparison, histone acetylation certainly regulates gene activity, but it is questionable whether this modification should be considered an epigenetic mechanism, because it is readily reversible, even without a cell division.

As DNA methylation and related epigenetic mechanisms are important for stably inherited gene silencing, other mechanisms must be responsible for stably inherited gene activation. Gene activation requires modification of chromatin in the regulatory regions of the gene and the assembly of a protein complex consisting of transcription factors binding to DNA at specific sites and co-activators. This complex interacts with basal transcription factors and RNA polymerases to initiate transcription, but also further modifies regional chromatin. It is clear that, but not entirely how active gene states are propagated through DNA replication and mitosis. Histone phosphorylation it thought to play a role. Another factor in this propagation is that cell differentiation is often achieved through transcription factor cascades which include an autoregulatory amplification step that make the process essentially irreversible. This could certainly be considered an epigenetic mechanism.

While the above mechanisms all occur esentially within the nucleus of a single cell, one could extend the concept of epigenetics to phenomena outside the nucleus and even to certain stable interactions between different cells. For instance, signals from one cell may elicit a response from another one which re-acts on the first and so on, until a stable steady-state is reached to which the system returns even after perturbations. Such signals are indeed exchanged in a homotypic or heterotypic fashion during normal tissue function and during tissue repair and adaptation. Intercellular loops are important in the regulation of tissue proliferation and differentiation and can be stably maintained throughout life. It does stretch the

Table 8.1. Some examples of epigenetic processes in humans

Accepted

Considered

Genomic imprinting

X-chromosome inactivation

Gene regulation by DNA methylation Posttranscriptional histone modification, specifically histone methylation

Posttranscriptional histone modification, specifically histone acetylation Regulation by polycomb and trithorax proteins Chromatin remodeling Autoregulatory transcription factor networks

Mutual paracrine cell-to-cell interaction networks

Stem cell specification and maintenance concept, but one could regard human embryonic development with some right as a sequence of epigenetic events.

Disturbances of each of the above mechanisms contribute to human cancers.

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