Epigenetics Of Cell Differentiation

Genetic changes like the loss of RB1 function or that of a chromatin remodeling protein like hSNF5/INI1 cause cancer by obliteration of epigenetic mechanism in which these proteins are involved. It is perhaps not incidential that the cancers caused in these instances impress primarily as failures of differentiation. One could go one step further and ponder whether some cancers might be caused by purely epigenetic mechanisms and represent a specific, if aberrant form of cell differentiation. This idea is, in fact, the core of an older theory that is now obsolete as a consequence of the discovery of the multitude of genetic changes present in the great majority of human cancers. So, if any human cancers are caused purely by epigenetic mechanisms, they are rare. Most likely, they would be childhood cancers characterized by failed differentiation. Some cases of Wilms tumors may come close ( >11-3).

However, the theory contained an important core of truth which is still relevant and may in fact now be understudied. Cell differentiation and cancer development resemble each other in that for a large number of genes 'cell-type-specific' patterns of expression, including strong activation as well as strict silencing must be stably established. It is plausible that the same mechanisms might be at work in both processes. These mechanisms are now partly understood for gene silencing in cancer cells (^8.4). By comparison, it is hardly known how overexpression of genes in cancer cells is established by epigenetic mechanisms.

For instance, overexpression of the EGFR is an important step in the progression of many carcinomas. In some cases, this overexpression is due to gain of chromosome 7p or regional amplification at 7p12, but these alterations are not generally found in cancers with overexpression of the protein. So, overexpression is likely caused by deregulation of gene expression secondary to alterations in other genes. For instance, degradation of the EGFR requires the CBL protein which could be lacking or the protein could be stabilized as a consequence of altered phosphorylation by PKC enzymes (^6.5). Still another possibility is that the ERBB1 gene encoding the receptor is locked in an activated state by epigenetic mechanisms, comparable to the silenced state of a tumor suppressor gene established by promoter hypermethylation (^8.3).

For the establishment and maintenance of an active gene state across cell division, the continuous presence of transcriptional activators is necessary. Current understanding is that transcriptional activators binding to promoter and enhancer sequences recruit co-activators to form a large protein complex, a transcriptosome, which modifies the local chromatin and guides the actual transcriptional apparatus including RNA polymerase. This local chromatin state is transmitted through mitosis in a largely unknown fashion.

In any case, the differentiation state of a cell strictly depends on the pattern of transcriptional activators expressed. Cell differentiation often involves cascades of transcription factors which successively activate each other. These cascades often involve autoregulatory loops that make the process essentially irreversible.One well-studied example is myoblast differentiation (Figure 8.8). It is initiated and carried through by muscle-specific transcription factors (MSTFs or MRFs) that belong to the basic helix-loop-helix family (bHLH) like the MYC proteins (^4.3). Like these, they bind to specific DNA sequences called E-boxes. The best-known of these factors is MYOD. E-boxes are present in genes encoding the typical proteins of muscle cells, but also in the enhancers of the genes encoding the MRFs. So, activation of MRFs beyond a threshhold leads to an autocatalytic cascade, in which several MRFs become expressed at increasing levels until full differentiation is achieved. The threshhold may be determined by the expression of MYC factors, but also by specialized inhibitor proteins, called ID. The four small ID proteins belong to the same general class of proteins as MRFs and MYC proteins, but lack a DNA-binding domain. Rather, they heterodimerize with and block the action of cell-type specific bHLH transcription factors. Overexpression of ID proteins, sometimes as a consequence of gene amplification, is a common finding in human cancers, particularly in carcinomas.

Importantly, transcription factor cascades not only lead to expression of cell-type specific products during normal cell differentiation, but also turn off cell

Figure 8.8 An autocatalytic transcription factor cascade during cell differentiation An interaction of pro-proliferative (MYC, IDs) and cell-type specific (MYOD, MTF) basic helix-loop-helix proteins regulates the terminal differentiation of myoblasts. The (simplified) autocatalytic loop between MYOD and other myoblast-specific transcription factors (MTF) at the center of the figure is responsible for the irreversibility of the process.

Figure 8.8 An autocatalytic transcription factor cascade during cell differentiation An interaction of pro-proliferative (MYC, IDs) and cell-type specific (MYOD, MTF) basic helix-loop-helix proteins regulates the terminal differentiation of myoblasts. The (simplified) autocatalytic loop between MYOD and other myoblast-specific transcription factors (MTF) at the center of the figure is responsible for the irreversibility of the process.

proliferation by interacting with cell cycle regulators. In muscle cells, cell proliferation and differentiation are mutually exclusive. MYOD not only competes with MYC, but also represses the transcription of the AP1 factors FOS and JUN in differentiated cells, while in proliferating myoblasts the reverse occurs. So this system tends to be either in one (proliferation) or the other (differentiation) state. In addition, RB1 is activated during muscle differentiation and inactivates E2F-dependent promoters required for cell proliferation, while supporting the action of MYOD.

Similar transcription factor networks are thought to act in the differentiation of other cell types. For instance, in the differentiation of hepatocytes, insulin-producing cells of the pancreas, and proximal tubule cells of the kidney, the transcriptional activators HNF4 and HNF1 may be organized in a mutually activatory autocatalytical loop stabilizing the differentiated phenotype.

In many cell types, retinoids contribute to differentiation and growth arrest. Retinoids activate one of several retinoic acid receptors, named RARa, P, or y, which are organized in an autocatalytic cascade. The RARB2 gene promoter contains a sequence, named a RARE (retinoic acid responsive element), to which retinoic acid receptors can bind and increase transcription of the gene. During differentiation induced by retinoic acid, one of the other receptors (a or y, depending on the cell type) initiates transcription of RARp, which amplifies its own induction. Loss of the initiating RAR or inactivation of the RARB gene blocks the cascade. Accordingly, a translocation linking RARa to a repressor domain blocks the differentiation of promyeloid cells in an acute leukemia (^10.5). In different carcinomas, the retinoid activatory cascade is interrupted by hypermethylation of the RARB2 promoter.

In summary, then, disruption of epigenetic mechanism leading to cell differentiation is an important component in cancer development. Conversely, cancer cells may set up their own epigenetic cascades that maintain a status of gene expression compatible with continuous tumor growth.

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