The groundbreaking discovery that overexpressing four embryonic transcription factors is sufficient to reprogram terminally differentiated fibroblasts into induced pluripotent stem (iPS) cells, which resemble embryonic stem cells, demonstrated the possibility to reverse cellular differentiation, a process known as reprogramming. This was first reported in 2006 for mouse fibroblasts and in 2007 for human fibroblasts, and subsequently for additional cell types.
The iPS cells exhibit the ability to differentiate into many cell types and the capacity for infinite self-renewal. In addition to unveiling details about the molecular basis of differentiation and about mechanisms that allow cells to maintain their identity, this finding opened novel therapeutic opportunities, including the possibility to generate patient-specific embryonic stem cells for use in regenerative medicine and to treat various conditions.
The ability of physical, chemical, biological, and socio-emotional factors to change gene expression by epigenetic modifications has opened a fascinating chapter in biology. Ultraviolet B exposure, previously known to induce mutations, was shown to cause DNA hypermethylation and to transcriptionally downregulate tumor-suppressor genes.
In many instances, these links provide the mechanistic basis for epidemiological observations made decades ago. For example, divalent nickel compounds have long been implicated in carcinogenesis based on animal and human epidemiological studies, even though they do not appear to be strong mutagens in vitro, suggesting that carcinogenesis may also occur by nongenotoxic pathways.
Divalent nickel salts were shown to cause epigenetic changes that include aberrant DNA methylation and post-translational histone modifications, causing changes in chromosomal condensation and gene silencing. These findings also illustrate that, for a long time, we erroneously visualized carcinogens as being mutagens, and neglected to consider the possibility that gene expression changes may occur by mechanisms that do not involve mutagenesis.
This fallacious strategy, similar to searching for the lost keys only under the lamp, because that is where the light reaches, was relevantly called, by Trosko and Upham, the “lamp post effect.”
In 2012, it was reported that slightly over 20% of all human cancers are causally linked to infectious diseases, and epigenetics played a pivotal role in rekindling and providing a mechanistic understanding of this link, which was first reported over a century ago but subsequently fell into oblivion for decades. These advances helped characterize the “epigenetic field for cancerization” or “epigenetic field defect,” a region with aberrant CpG methylation that has a higher likelihood of undergoing malignant transformation.
An epigenetic field for cancerization was visualized after exposure to various carcinogens, and was reported for multiple malignant tumors, including stomach, breast, liver, and colon cancer.