Epigenetic Reprogramming

Reprogramming refers to erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development says Jacob Hanna from the Jacob Hanna Lab. 

After fertilization some cells of the newly formed embryo migrate to the germinal ridge and will eventually become the germ cells (sperm and oocytes). Due to the phenomenon of genomic imprinting, maternal and paternal genomes are differentially marked and must be properly reprogrammed every time they pass through the germline. Therefore, during the process of gametogenesis the primordial germ cells must have their original biparental DNA methylation patterns erased and re-established based on the sex of the transmitting parent.

After fertilization the paternal and maternal genomes are once again demethylated and remethylated (except for differentially methylated regions associated with imprinted genes). This reprogramming is likely required for totipotency of the newly formed embryo and erasure of acquired epigenetic changes. In vitro manipulation of pre-implantation embryos has been shown to disrupt methylation patterns at imprinted loci and plays a crucial role in cloned animals.

Reprogramming can also be induced artificially through the introduction of exogenous factors, usually transcription factors. In this context, it often refers to the creation of induced pluripotent stem cells from mature cells such as adult fibroblasts. This allows the production of stem cells for biomedical research, such as research into stem cell therapies, without the use of embryos. It is carried out by the transfection of stem-cell associated genes into mature cells using viral vectors such as retroviruses.

Epigenetic Reprogramming in Plant and Animal Development

Epigenetic modifications of the genome are generally stable in somatic cells of multicellular organisms. In germ cells and early embryos, however, epigenetic reprogramming occurs on a genome-wide scale, which includes demethylation of DNA and remodeling of histones and their modifications.

The mechanisms of genome-wide erasure of DNA methylation, which involve modifications to 5-methylcytosine and DNA repair, are being unraveled. Epigenetic reprogramming has important roles in imprinting, the natural as well as experimental acquisition of totipotency and pluripotency, control of transposons, and epigenetic inheritance across generations.

Small RNAs and the inheritance of histone marks may also contribute to epigenetic inheritance and reprogramming. Reprogramming occurs in flowering plants and in mammals, and the similarities and differences illuminate developmental and reproductive strategies.

Epigenetic Reprogramming Therapy

In addition to genetic changes, epigenetic aberrations also play important roles in radiation- and chemical-induced disorders and carcinogenesis. The present study investigated whether epigenetic therapy with a histone deacetylase (HDAC) inhibitor has dual benefits for radiation-induced oral mucositis and chemical-induced oral carcinogenesis, which should be treated at the same time.

The HDAC inhibitor phenylbutyrate was tested to determine if it influences DNA repair and survival in irradiated normal cells by examining the patterns and dynamics of γH2AX foci and γH2AX-Rad51 co-localization and using clonogenic assays. Oral mucositis or carcinogenesis was induced in hamsters using irradiation or dimethylbenzylamine (DMBA) irritation of the cheek pouch. The ability of phenylbutyrate formed in proper carriers to prevent radiation-induced mucositis and inhibit chemical-induced oral carcinogenesis was assessed. The treated or untreated irradiated or DMBA-irritated oral tissues were examined by histology and immunohistochemistry or subjected to gene expression analysis using real-time RT-PCR.

Epigenetic therapy using the HDAC inhibitor as an adjuvant to radiotherapy for chemical-induced oral cancer may provide a promising strategy combining the prevention of radiation-induced oral mucositis and the inhibition of oral carcinogenesis.