• Top: Normal dynamic of histone acetylation leads to open and closed chromatin genome-wide and changes in gene expression.
• Middle: HDAC inhibition repressed the closed-open change favoring an open chromatin state and gene expression.
• Bottom: Epigenetic priming general model. Starting with an hypothetical closed chromatin state a priming stimuli sensitizes the chromatin to other stimuli and subsequently increase transcription

Epigenetic priming (also known as gene priming) is the modification to a cell's epigenome whereby specific chromatin domains within a cell are converted from a closed state to an open state, usually as the result of an external biological trigger or pathway, allowing for DNA access by transcription factors or other modification mechanisms. The action of epigenetic priming for a certain region of DNA dictates how other gene regulation mechanisms will be able to act on the DNA later in the cell’s life. Epigenetic priming has been chiefly investigated in neuroscience and cancer research, as it has been found to play a key role in memory formation within neurons^[1] and tumor-suppressor gene activation in cancer treatment^[2] respectively.

Mechanism

Epigenetic priming refers to a latent epigenetic state triggered by a stimuli, such as a drug or environmental changes. The epigenetically primed state is characterized by chromatin loosening, which is the change of chromatin state from heterochromatin (tightly bound and inaccessible) to euchromatin (loosely bound and fully accessible), which leads to an increased transcription of certain genes as a result of the easier access and binding of transcription factors.^[1] The triggering signal is effectuated by various epigenetic mechanisms, the most prominent of which are histone acetylation and histone methylation. Most of the epigenetic agents involved in histone modifications, such as histone deacetylase (HDAC) variants, are non-targeted, meaning the loosening and tightening of the chromatin is unspecific within the cell.^[3] Therefore, epigenetic priming and resultant gene transcription occurs throughout the cell and affects a large variety of chromatin sites.

Chromatin remodeling processes such as histone acetylation and methylation are reversible, and euchromatin sites resulting from epigenetic priming are eventually converted back to heterochromatin by reversal agents such as histone deacetylase. Thus, priming may be artificially controlled by inhibiting these reversal agents within the cell so that the chromatin remains open. Among these approaches, the most well studied is HDAC inhibition.

Cancer

Cancer cell sensitization to treatment through epigenetic priming. Normal cells with activated tumor suppressor genes (TSG) and Cancer cell with inactivated TSG through epigenetic mechanisms (showing only acetylation for simplification purposes). Priming stimuli performed with DNMT and/or HDAC inhibitors following by immunotherapy treatment (second stimuli) leading to reactivation of TSG.

Epigenetic priming was first described in cancer research when epigenetic alterations on tumor-suppressor genes (TSG) were found to be drivers of carcinogenesis.^[2] Epigenetic alterations (e.g. DNA methylation) resulting in TSG inactivation as a common means of tumor formation. Contrary to regular DNA mutations common in cancer, methylation is reversible, provided that the chromatin is adequately open to allow hypomethylating agents to access the DNA and prevent methylation. Therefore, priming was investigated as a ‘pre-treatment’ to sensitize the tumerogenic cells to hypomethylating chemotheraputics such as decitabine.^[2] Many types of cancer (e.g. gastric) are known for having aberrant epigenetic changes, particularly in DNA methylation. In contrast to DNA mutations which cannot be easily changed through treatment, these aberrant epigenetic changes allow for a reversible treatment avenue.

Epigenetic agents have proved to increase expression of aberrantly silenced genes (i.e. Runx3, Tnf, Pycard, Fas) in mice models after 5-aza-CR treatment .^[4] Thus, helping overcome cancer-induced cell dysfunction. Additionally, epigenetic priming has been shown to enhance cytotoxicity of cancer drugs (i.e. SN38 and CDDP), showing promising results in lung and ovarian cancer.^[5] Due to their proven effectivity, the FDA approved 5-azacytidine, romidepsin and other DMNT inhibitors (i.e. 5-azacytidine, hydralazine, 5-Aza-2’-deoxycytidine) and HDAC inhibitors (i.e. romidepsin, belinostat, panobinostat) for clinical use .^{[4] [6]}

Neuroscience

It is believed that epigenetic modifications, and in particular those which perform epigenetic priming, are fundamentally responsible for the encoding of memory within neurons. This idea is supported by various pieces of evidence. Firstly, despite inhibition of protein synthesis during memory formation, memories may be retrieved later on.^[11] This, along with the discovery that long-term memory can be restored after synapse deterioration,^[12] suggests synaptic structuring (which requires protein synthesis during memory formation) is not the fundamental source of engram encoding within a cell.^[13] Furthermore, in mice it has been found that proper histone acetytransferase function is required for memory formation^[14][15] and that HDAC inhibition in neurons can improve learning behavior and long-term memory.^[16] An explanation is that, when present in combination with memory-associated neural activity, HDAC inhibitors (HDACi) allow chromatin to remain open and increase transcription of genes that remodel synapses, resulting in increased plasticity and improved memory formation.^[13][17] As a result of these observations, it has been proposed that epigenetic priming is the initial phase of memory formation.^[13]

It has been found that different forms of long-term memory are associated with different types of histone acetylation, such as acetylation of H3 versus H4.^[15] This suggests that epigenetic priming in neurons which result in different memory profile expressions may be encoded by different histone acetyltransferases. Thus, although the mechanisms that loosen chromatin are unspecific in their target, likely have specificity depending on which ones are activated. In a similar vein, it is believed that the action of different of priming agents, such as the varieties of histone acetyltransferases, may combine to create a stacking effect on neuron chromatin, resulting in significantly increased expression of the associated genes.

Metabolic syndrome

Epidemiological and experimental studies have shown that environmental factors during early development, such as maternal nutrition and body composition, can influence the metabolic phenotype of the offspring.^[18] Epigenetic priming is thought to mediate the persistent changes in gene expression that could eventually lead to metabolic syndrome.^[19] Potentially, these induced metabolic disruptions benefit progeny developing in a low resources environment to increased success later in life.^[18] The Agouti mouse exemplifies a variation of the aforementioned effect of early environmental exposures on offspring’s fitness.^[20]

References