and inactivation of tumor suppressor genes has been observed. frequently observed in lung cancer is the methylation of gene promoters that are involved in critical functions like cell-cycle control, repairing dna, cell adhesion, proliferation, apoptosis, and motility. a few of the common genes frequently observed are apc, cdh1, cdkn2a, mgmt, and rassf1a (a tumor suppressor). in the cases of cdkn2a and rassf1a dna these genes are methylated, resulting in the loss of tumor suppressor genes. various strategies such as using drugs like entinostat and azacitidine have been observed in clinical trials of non-small-cell lung carcinoma. the idea being that etinostat, a histone deacetylase inhibitor, can prevent the silencing of genes by allowing them to be accessible to transcription machinery. azacitidine can be metabolized and incorporated into dna and then recognized as a substrate for dna methyltransferases, but since the enzyme is bound the methyltransferase cannot add methylation marks and thus silence crucial genes. heart failure histone modifications, dna methylation, and micrornas have been found to play an important role in heart disease. previously, histone tail acetylation has been linked to cardiac hypertrophy or abnormal heart muscle thickening that is usually due to an increase in cardiomyocyte size or other cardiac muscle changes. the hypertrophic changes that occur in cardiac muscles cells result from the required acetylation of histone tails via acetyltransferases. in addition to acetyltransferases, histone deacetylases (hdacs) also aid in the regulation of muscle cells. class ii hdacs 5 and 9 inhibit the activity of a factor known as myocyte enhancer factor 2 (mef2), which unable to bind prevents the expression of genes that produce hypertrophic effects. additionally, loci such as pecam1, amotl2 and arhgap24 have been seen with different methylation patterns that are correlated with altered gene expression in cardiac tissue. there are an increasing number of scientific publications that are finding that mirna plays a key role in various aspects of heart failure. examples of functions for mirna include the regulation of the cardiomyocyte cell cycle and regulation of cardiomyocyte cell growth. knowing the epigenetic modifications allows for the potential use of drugs to modify the epigenetic status of a target sequence. one could possibly target the mirnas using antagomirs. antagomirs are single strand rnas that are complementary, which have been chemically engineered oligonucleotides that silence mirnas so that they cannot degrade the mrna that is needed for normal levels of expression. dna methylation of cpgs can lead to a reduction of gene expression, and in some cases this decrease in gene product can contribute to disease. therefore, in those instances it is important to have potential drugs that can alter the methylation status of the gene and increase expression levels. to increase gene expression, one may try to decrease cpg methylation by using a drug that works as dna methyltransferase inhibitor such as decitabine or 5-aza-2'-deoxycytidine. on the other hand, some diseases result from a decrease in acetylase activity, which results in a decrease in gene expression. some studies have shown that inhibiting hdac activity can attenuate cardiac hypertrophy. trichostatin a and sodium butyrate are two hdac inhibitors. trichostatin a is known for its ability to inhibit class i and ii hdacs from removing acetylases and decreasing gene expression. sodium butyrate is another chemical that inhibits class i hdacs, thus resulting in the ability for transcription factors to easily access and express the gene. challenges in development of epigenetic therapies there are a number of challenges with the developing epigenetic therapies for widespread medical use. while laboratory results indicate relationships between genes and potential drug interactions that could mitigate the effects of mutations, the complexity of the human genome and epigenome makes it difficult to develop therapies that are safe, efficient, and consistent. epigenetic alteration may affect more systems than the target genes, which gives potential for deleterious effects to rise out of treatment. additionally, epigenetic mutations can be a result of lineage. as tissue gene expression is largely regulated by epigenetic interactions, certain tissue-specific cancers are difficult to target with epigenetic therapies. additionally, genes that encode for elements that prevent one type of cancer in a cell, may have altered function in another and lead to another type of cancer. trying to modify these proteins, such as ezh2, may give rise to other types of cancer. selectivity is another hurdle in the development of therapies. since many proteins are structurally similar, especially within the same protein family, broad-spectrum inhibitors can't always be used since modifying the regulation of one protein may do the same to others in the family. based on the differences in these epigenetic patterns, scientists and physicians can further predict the drug response of each patient. one of the most compelling examples is methylation of the tumor suppressor gene at promoter sequence that codes for mgmt. mgmt is a dna repair protein responsible for transferring methyl groups from o(6)-alkylguanine in dna to itself to fight against mutagenesis and the buildup of toxic compounds that result from alkylating agents. therefore, mgmt is responsible for the repair of areas that have been damaged by toxins. this mgmt promoter region has been found to be highly methylated, and thereby repressed, in patients with various types of cancer. several drugs such as procarbazine, streptozotocin, bcnu (carmustine), and temozolamide are designed to remodel dna to reverse this abnormal methylation modification so that mgmt may be normally expressed and repair dna. the methylation status of the promoter become the best predictor of responses to bcnu and temozolamide in patients with brain cancer. epigenetic inhibitors and therapies bromodomain and inhibitors (bet inhibitor) proteins containing bromodomains recognize and bind acetylated lysine residues in histones, causing chromatin structure modification and a subsequent shift in levels of gene expression. bromodomain and extra-terminal (bet) proteins bind acetyl groups and work with rnapii to help with transcription and elongation of chromatin. bet inhibitors have been able to prevent successful interaction between bet proteins and acetylated histones. using a bet inhibitor can reduce the over expression of bromodomain proteins, which can cause aberrant chromatin remodeling, transcription regulation, and histone acetylation. histone acetylase inhibitors several studies have shown that histone acetyltransferase (hat) inhibitors are useful in re-inducing expression of tumor suppression genes by stopping histone acetyltransferase activity to prevent chromatin condensation. protein methyltransferase (pmt) inhibitors: pmt's play a key role in methylating lysine and arginine residues to affect transcription levels of genes. it has been suggested that their enzymatic activity plays a role in cancer, as well as neurodegenerative and inflammatory diseases. histone deacetylase inhibitors using histone deacetylase (hdac) inhibitors allows for genes to remain transcriptionally active. hdaci's have been used in various autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and systemic onset juvenile idiopathic arthritis. they have also proven useful for treating cancer, since they are structurally diverse and only effect 2-10% of expressed genes. using hdac inhibitors for the treatment of psychiatric and neurodegenerative diseases has shown promising results in early studies. additionally, studies have demonstrated that hdaci are useful in minimizing damage after a stroke, and encouraging angiogenesis and myogenesis in embryonic cells. dna methyltransferase inhibitors one of the common characteristics of various types of cancer is hypermethylation of a tumor suppressing gene. repression of this methyltransferase action at targeted loci can prevent recurring transfer of methyl groups to these sites and keep them open to transcriptional machinery, allowing more tumor-suppression genes to be made. these drugs are typically cytidine derivatives. these drugs tether dnmt to the dna and prevent their continued action. treatments that inhibit dnmt function without attachment to dna (which can cause toxic effects) show they could be effective treatment options but they are not developed enough to see widespread use.