Antisense RNA

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AsRNA is transcribed from the lagging strand of a gene and is complementary to a specific mRNA or sense transcript. Figure1 Definition of antisense RNAs (asRNAs) .png
AsRNA is transcribed from the lagging strand of a gene and is complementary to a specific mRNA or sense transcript. 

Antisense RNA (asRNA), also referred to as antisense transcript, [1] natural antisense transcript (NAT) [2] [3] [4] or antisense oligonucleotide, [5] is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and thereby blocks its translation into protein. The asRNAs (which occur naturally) have been found in both prokaryotes and eukaryotes, [1] and can be classified into short (<200 nucleotides) and long (>200 nucleotides) non-coding RNAs (ncRNAs). [4] The primary function of asRNA is regulating gene expression. asRNAs may also be produced synthetically and have found wide spread use as research tools for gene knockdown. They may also have therapeutic applications. [6] [1] [4]

Contents

Discovery and history in drug development

Some of the earliest asRNAs were discovered while investigating functional proteins. An example was micF asRNA. While characterizing the outer membrane porin ompC in E.coli, some of the ompC promoter clones observed were capable of repressing the expression of other membrane porin such as ompF. The region responsible for this repression function was found to be a 300 base-pair locus upstream of the ompC promoter. This 300 base-pair region is 70% homologous in sequence with the 5' end of the ompF mRNA and thus the transcript of this 300 base pair locus was complementary to the ompF mRNA. Later on, this transcript, denoted micF, was found to be an asRNA of ompF and capable of downregulating the expression of ompF under stress by forming a duplex with the ompF mRNA. This induces the degradation of the ompF mRNA. [2]

Unlike micF RNA being discovered by accident, the majority of asRNAs were discovered by genome wide searches for small regulatory RNAs and by transcriptome analysis. Conventionally, the first step involves computational predictions based on some known characteristics of asRNAs. During computational searches, the encoding regions are excluded. The regions that are predicted to have conserved RNA structures and act as orphan promoters and Rho independent terminators are preferenced during analysis. Because computational searches focuses on the intergenic region, the asRNAs that are transcribed from the opposite strand of an encoding gene are likely to be missed using this method. To detect asRNA transcribed from the encoding region, oligonucleotide microarrays can be used. In this method, one or both strands of encoding genes can be used as probes. In addition to computational searches and microarrays, some asRNAs were discovered by sequencing cDNA clones as well as mapping promoter elements. [7] Although many findings from the approaches mentioned above gave rise to a lot of possible asRNAs, only few were proven to be actual asRNAs via further functional tests. To minimize the number of false positive results, new approaches from recent years have been focusing on strand-specific transcription, chromatin binding noncoding RNAs and single cell studies. [1]

The idea of asRNAs as drug targets started in 1978 when Zamecnik and Stephenson found an antisense oligonucleotide to the viral RNA of Rous scarcoma virus that was capable of inhibiting viral replication and protein synthesis. Since then, much effort has been devoted to developing asRNAs as drug candidates. In 1998, the first asRNA drug, fomivirsen, was approved by FDA. Fomivirsen, a 21 base-pair oligonucleotide, was developed to treat cytomegalovirus retinitis in patients with AIDS. It works by targeting the transcribed mRNA of the virus and consequently inhibiting replication of cytomegalovirus. Despite fomivirsen being discontinued in 2004 due to the loss of the market, it served as a successful and inspiring example of using asRNAs as drug targets or drug candidates. [5]

Another example of using an asRNA as a therapeutic agent is mipomersen, which was approved by FDA in 2013. Mipomersen was developed to manage the level of low-density lipoprotein cholesterol (LDL) in patients with homozygous familial hypercholesterolemia (HoFH), which is a rare autosomal dominant genetic condition. Because of the high level of total cholesterol (650–1000 mg/dL) and LDL receptor (above 600 mg/dL) in HoFH, patients with HoFH has a high risk for coronary heart disease. Because the protein apo-B-100 has been found to be required to produce very low-density lipoprotein (VLDL) and LDL, mipomersen complements with the mRNA of apo-B-100 and target it for RNAse H dependent degradation. Ultimately, mipomersen is able to reduce the level of LDL. [8]

Examples across species

The initial asRNAs discovered were in prokaryotes including plasmids, bacteriophage and bacteria. For example, in plasmid ColE1, the asRNA termed RNA I plays an important role in determining the plasmid copy number by controlling replication. The replication of ColE1 relies on the transcription of a primer RNA named RNA II. Once RNA II is transcribed, it hybridizes to its DNA template and later cleaved by RNase H. In the presence of the asRNA RNA I, RNA I and RNA II forms a duplex which introduces a conformational change of RNA II. Consequently, RNA II cannot hybridize with its DNA template which results in a low copy number of ColE1. In bacteriophage P22, the asRNA sar helps regulate between lytic and lysogenic cycle by control the expression of Ant. [9] Besides being expressed in prokaryotes, asRNAs were also discovered in plants. The most well described example of asRNA regulation in plants is on Flowering Locus C (FLC) gene. FLC gene in Arabidopsis thaliana encodes for a transcription factor that prevent expression of a range of genes that induce floral transition. In cold environment, the asRNA of FLC gene, denoted COOLAIR, is expressed and inhibits the expression of FLC via chromatin modification which consequently allows for flowering. [10] Another well studied example is DOG1 (Delay of Germination 1) gene. Its expression level is negatively regulated by the antisense transcript (asDOG1 or 1GOD) acting in cis. [11] In mammalian cells, a typical example of asRNA regulation is X chromosome inactivation. Xist, an asRNA, can recruit polycomb repressive complex 2 (PRC2) which results in heterochromatinization of the X chromosome. [3]

Classification

Antisense RNAs can be classified in different ways. In terms of regulatory mechanisms, some authors group asRNAs into RNA-DNA interactions, RNA-RNA interactions either in nucleus or cytoplasm and RNA-protein interactions (epigenetic). [3] Antisense RNAs can be categorized by the type of the promoters that initiate expression of asRNAs: independent promoters, shared bidirectional promoters or cryptic promoters. In terms of length, although asRNA in general is classified as lncRNAs, there are short asRNAs with length of less than 200 base pairs. Because the regulatory mechanism of asRNAs are found to be species specific, asRNAs can also be classified by species. [1] One of the common ways of classifying asRNAs is by where the asRNAs are transcribe relatively to their target genes: cis-acting and trans-acting.[ citation needed ]

Cis-acting

Cis-acting asRNAs are transcribed from the opposite strand of the target gene at the target gene locus. They often show high degree or complete complementarity with the target gene. If the cis-acting asRNA regulates gene expression by targeting mRNA, it can only target individual mRNA. Upon interactions with the targeting mRNAs, cis-acting asRNAs can either block ribosome binding or recruit RNAase to degrade the targeting mRNAs. Consequently, the function of these cis-acting asRNAs is to repress translation of the targeting mRNAs. [2] Besides cis-acting asRNAs that target mRNAs, there are cis-acting epigenetic silencers and activators. Antisense RNA has been shown to repress the translation of LINE1-ORF2 domain of Entamoeba histolytica. However it is not confirmed yet whether its cis-acting or trans. [12]

In terms of epigenetic modification, cis-acting refers to the nature of these asRNAs that regulate epigenetic changes around the loci where they are transcribed. Instead of targeting individual mRNAs, these cis-acting epigenetic regulators can recruit chromatin modifying enzymes which can exert effects on both the transcription loci and the neighboring genes. [3]

Trans-acting

Trans-acting asRNAs are transcribed from loci that are distal from the targeting genes. In contrast to cis-acting asRNAs, they display low degree of complementarity with the target gene but can be longer than cis-acting asRNAs. They can also target multiple loci. Because of these properties of trans-acting asRNAs, they form less stable complexes with their targeting transcripts and sometimes require aids from RNA chaperone protein such as Hfq to exert their functions. Due to the complexity of the trans-acting asRNAs, they are currently considered to be less druggable targets. [2]

Function

'Epigenetic regulation:' a) AsRNAs can induce DNA methylation by recruiting a DNA methyltransferase (DNMT). b) AsRNAs can induce histone methylation by recruiting of a histone methyltransferase (HMT). 'Co-transcriptional regulation:' c) AsRNAs can cause RNA polymerase (Pol) collision and stop the transcription. d) AsRNAs can preference translation of a specific splice variant (mRNA V1) by blocking the other splice variant (mRNA V2). 'Post-transcriptional regulation:' e) AsRNA-mRNA duplex can either block ribosome from binding to the mRNA or recruit RNase H to degrade the mRNA. By this mechanism, asRNAs directly inhibit translation of the mRNAs. Figure 2 Mechanism of gene repression by asRNAs. .png
'Epigenetic regulation:' a) AsRNAs can induce DNA methylation by recruiting a DNA methyltransferase (DNMT). b) AsRNAs can induce histone methylation by recruiting of a histone methyltransferase (HMT). 'Co-transcriptional regulation:' c) AsRNAs can cause RNA polymerase (Pol) collision and stop the transcription. d) AsRNAs can preference translation of a specific splice variant (mRNA V1) by blocking the other splice variant (mRNA V2). 'Post-transcriptional regulation:' e) AsRNA-mRNA duplex can either block ribosome from binding to the mRNA or recruit RNase H to degrade the mRNA. By this mechanism, asRNAs directly inhibit translation of the mRNAs.

Epigenetic regulation

Many examples of asRNAs show the inhibitory effect on transcription initiation via epigenetic modifications.

DNA methylation

DNA methylation can result in long term downregulation of specific genes. Repression of functional proteins via asRNA induced DNA methylation has been found in several human disease. In a class of alpha-thalassemia, a type of blood disorder that has reduced level of hemoglobin leading to insufficient oxygen in the tissues, [13] hemoglobin alpha1 gene (HBA1) is downregulated by an abnormal transcript of putative RNA-binding protein Luc7-like (LUC71) that serves as an asRNA to HBA1 and induces methylation of HBA1's promoter. [1] Another example is silencing of a tumor suppressor gene p15INK4b, also called CDKN2B, in acute lymphoblastic leukemia and acute myeloid leukemia. The asRNA that is responsible for this silencing effect is antisense non-coding RNA in the INK locus (ANRIL), which is expressed in the same locus that encodes for p15INK4b. [3]

Histone modification

In eukaryotic cells, DNA is tightly packed by histones. Modification on histones can change interactions with DNA which can further induce changes in gene expression. The biological consequences of histone methylation are context dependent. In general, histone methylation leads to gene repression but gene activation can also be achieved. [14] Evidence has shown histone methylation can be induced by asRNAs. For instance, ANRIL, in addition to the ability to induce DNA methylation, can also repress the neighboring gene of CDKN2B, CDKN2A, by recruiting polycomb repressive complex 2 (PRC2) which leads to histone methylation (H3K27me). Another classic example is X chromosome inactivation by XIST. [1]

ANRIL induced epigenetic modification is an example of cis acting epigenetic regulation. [3] In addition, Antisense RNA-induced chromatin modification can be both trans-acting. For example, in mammals, the asRNA HOTAIR is transcribed from homeobox C (HOXC) locus but it recruits PRC2 to HOXD which deposits H3K27 and silences HOXD. HOTAIR is highly expressed in primary breast tumors. [1]

Co-transcriptional regulation

Epigenetic regulations such as DNA methylation and histone methylation can repress gene expression by inhibiting initiation of transcription. Sometimes, however, gene repression can be achieved by prematurely terminating or slowing down transcription process. AsRNAs can be involved in this level of gene regulation. For example, in bacterial or eukaryotic cells where complex RNA polymerases are present, bidirectional transcription at the same locus can lead to polymerase collision and results in the termination of transcription. Even when polymerase collision is unlikely during weak transcription, polymerase pausing can also occur which blocks elongation and leads to gene repression. One of the examples is repression of IME4 gene by its asRNA RME2. Another way of affecting transcription co-transcriptionally is by blocking splicing. One classic example in human is zinc-finger E-box binding homeobox 2 gene (ZEB2) which encodes E-cadherin, a transcriptional repressor. Efficient translation of ZEB2 mRNA requires the presence of an internal ribosome entry site (IRES) in intron of the mRNA at the 5' end. With the asRNA of ZEB2 being expressed, it can mask the splicing site and maintain the IRES in the mRNA which results in an efficient synthesis of E-cadherin. Lastly, depending on the level of asRNA expression, different isoforms of the sense transcript can be produced. Therefore, asRNA dependent regulation is not limited to on/off mechanism; rather, it presents a fine tone control system. [1]

Post-transcriptional regulation

The direct post transcriptional modulation by asRNAs refers to mRNAs being targeted by asRNAs directly; thus, the translation is affected. Some characteristics of this type of asRNAs are described in the cis- and trans- acting asRNAs. This mechanism is relatively fast because both the targeting mRNA and its asRNA need to be present simultaneously in the same cell. As described in the cis-acting asRNAs, the mRNA-asRNA pairing can result in blockage of ribosome entry and RNase H dependent degradation. Overall, mRNA-targeting asRNAs can either activate or inhibit translation of the sense mRNAs with inhibitory effect being the most abundant. [1]

Therapeutic potential

As a regulatory element, asRNAs bear many advantages to be considered as a drug target. First of all, asRNAs regulate gene expression at multiple levels including transcription, post-transcription and epigenetic modification. Secondly, the cis-acting asRNAs are sequence specific and exhibits high degree of complementarity with the targeting genes. [1] Thirdly, the expression level of asRNAs is very small compared to that of the targeting mRNAs; therefore, only small amount of asRNAs is required to produce an effect. In terms of drug targets, this represents a huge advantage because only a low dosage is required for effectiveness. [4]

Recent years the idea of targeting asRNAs to increase gene expression in a locus specific manner has been drawing much attention. Due to the nature of drug development, it is always easier to have drugs functioning as downregulators or inhibitors. However, there is a need in developing drugs that can activate or upregulate gene expression such as tumor suppressor genes, neuroprotective growth factors and genes that are found silenced in certain Mendelian disorders. Currently, the approach to restore deficient gene expression or protein function include enzyme replacement therapies, microRNA therapies and delivery of functional cDNA. However, each bears some drawbacks. For example, the synthesized protein used in the enzyme replacement therapies often cannot mimic the whole function of the endogenous protein. In addition, enzyme replacement therapies are life-long commitment and carry a large financial burden for the patient. Because of the locus specific nature of asRNAs and evidences of changes in asRNA expression in many diseases, there have been attempts to design single stranded oligonucleotides, referred as antagoNATs, to inhibit asRNAs and ultimately to increase specific gene expression. [4]

Despite the promises of asRNAs as drug targets or drug candidates, there are some challenges remained to be addressed. [15] First of all, asRNAs and antagoNATs can be easily degraded by RNase or other degrading enzymes. To prevent degradation of the therapeutic oliogoneucleotides, chemical modification is usually required. The most common chemical modification on the oligonucleotides is adding a phosphorothioate linkage to the backbones. [5] However, the phosphrothioate modification can be proinflammatory. Adverse effects including fever, chills or nausea have been observed after local injection of phosphrothioate modified oligonucleotides. Secondly, off target toxicity also represents a big problem. Despite the locus-specific nature of the endogenous asRNAs, only 10–50% synthesized oligonucleotides showed expected targeting effect. One possible reason for this problem is the high requirement on the structure of the asRNAs to be recognized by the target sequence and RNase H. A single mismatch can result in distortion in the secondary structure and lead to off target effects. [4] Lastly, artificial asRNAs have been shown to have limited intracellular uptake. [5] Although neurons and glia have been shown to have the ability to freely uptake naked antisense oligonucleotides, a traceable carriers such as virus and lipid vesicles would still be ideal to control and monitor the intracellular concentration and metabolism. [4]

See also

Related Research Articles

<span class="mw-page-title-main">Epigenetics</span> Study of DNA modifications that do not change its sequence

In biology, epigenetics is the study of stable changes in cell function that do not involve alterations in the DNA sequence. The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic basis for inheritance. Epigenetics most often involves changes that affect the regulation of gene expression, and that persist through cellular division. Such effects on cellular and physiological phenotypic traits may result from external or environmental factors, or be part of normal development. It can also lead to diseases such as cancer.

<span class="mw-page-title-main">Gene expression</span> Conversion of a genes sequence into a mature gene product or products

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, and ultimately affect a phenotype. These products are often proteins, but in non-protein-coding genes such as transfer RNA (tRNA) and small nuclear RNA (snRNA), the product is a functional non-coding RNA. Gene expression is summarized in the central dogma of molecular biology first formulated by Francis Crick in 1958, further developed in his 1970 article, and expanded by the subsequent discoveries of reverse transcription and RNA replication.

<span class="mw-page-title-main">Transcription (biology)</span> Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called non-coding RNAs (ncRNAs). mRNA comprises only 1–3% of total RNA samples. Less than 2% of the human genome can be transcribed into mRNA, while at least 80% of mammalian genomic DNA can be actively transcribed, with the majority of this 80% considered to be ncRNA.

A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and viruses.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

<span class="mw-page-title-main">Regulation of gene expression</span> Modifying mechanisms used by cells to increase or decrease the production of specific gene products

Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products. Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.

<span class="mw-page-title-main">Primary transcript</span> RNA produced by transcription

A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs are modified in preparation for translation. For example, a precursor mRNA (pre-mRNA) is a type of primary transcript that becomes a messenger RNA (mRNA) after processing.

In molecular biology and genetics, the sense of a nucleic acid molecule, particularly of a strand of DNA or RNA, refers to the nature of the roles of the strand and its complement in specifying a sequence of amino acids. Depending on the context, sense may have slightly different meanings. For example, negative-sense strand of DNA is equivalent to the template strand, whereas the positive-sense strand is the non-template strand whose nucleotide sequence is equivalent to the sequence of the mRNA transcript.

<span class="mw-page-title-main">Eukaryotic transcription</span> Transcription is heterocatalytic function of DNA

Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of transportable complementary RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Unlike prokaryotic RNA polymerase that initiates the transcription of all different types of RNA, RNA polymerase in eukaryotes comes in three variations, each translating a different type of gene. A eukaryotic cell has a nucleus that separates the processes of transcription and translation. Eukaryotic transcription occurs within the nucleus where DNA is packaged into nucleosomes and higher order chromatin structures. The complexity of the eukaryotic genome necessitates a great variety and complexity of gene expression control.

<span class="mw-page-title-main">Histone-modifying enzymes</span> Type of enzymes

Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins, which then join to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression.

Natural antisense transcripts (NATs) are a group of RNAs encoded within a cell that have transcript complementarity to other RNA transcripts. They have been identified in multiple eukaryotes, including humans, mice, yeast and Arabidopsis thaliana. This class of RNAs includes both protein-coding and non-coding RNAs. Current evidence has suggested a variety of regulatory roles for NATs, such as RNA interference (RNAi), alternative splicing, genomic imprinting, and X-chromosome inactivation. NATs are broadly grouped into two categories based on whether they act in cis or in trans. Trans-NATs are transcribed from a different location than their targets and usually have complementarity to multiple transcripts with some mismatches. MicroRNAs (miRNA) are an example of trans-NATs that can target multiple transcripts with a few mismatches. Cis-natural antisense transcripts (cis-NATs) on the other hand are transcribed from the same genomic locus as their target but from the opposite DNA strand and form perfect pairs.

<span class="mw-page-title-main">Long non-coding RNA</span> Non-protein coding transcripts longer than 200 nucleotides

Long non-coding RNAs are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein. This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as microRNAs (miRNAs), small interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. Given that some lncRNAs have been reported to have the potential to encode small proteins or micro-peptides, the latest definition of lncRNA is a class of RNA molecules of over 200 nucleotides that have no or limited coding capacity. Long intervening/intergenic noncoding RNAs (lincRNAs) are sequences of lncRNA which do not overlap protein-coding genes.

Epigenomics is the study of the complete set of epigenetic modifications on the genetic material of a cell, known as the epigenome. The field is analogous to genomics and proteomics, which are the study of the genome and proteome of a cell. Epigenetic modifications are reversible modifications on a cell's DNA or histones that affect gene expression without altering the DNA sequence. Epigenomic maintenance is a continuous process and plays an important role in stability of eukaryotic genomes by taking part in crucial biological mechanisms like DNA repair. Plant flavones are said to be inhibiting epigenomic marks that cause cancers. Two of the most characterized epigenetic modifications are DNA methylation and histone modification. Epigenetic modifications play an important role in gene expression and regulation, and are involved in numerous cellular processes such as in differentiation/development and tumorigenesis. The study of epigenetics on a global level has been made possible only recently through the adaptation of genomic high-throughput assays.

Cryptic unstable transcripts (CUTs) are a subset of non-coding RNAs (ncRNAs) that are produced from intergenic and intragenic regions. CUTs were first observed in S. cerevisiae yeast models and are found in most eukaryotes. Some basic characteristics of CUTs include a length of around 200–800 base pairs, a 5' cap, poly-adenylated tail, and rapid degradation due to the combined activity of poly-adenylating polymerases and exosome complexes. CUT transcription occurs through RNA Polymerase II and initiates from nucleosome-depleted regions, often in an antisense orientation. To date, CUTs have a relatively uncharacterized function but have been implicated in a number of putative gene regulation and silencing pathways. Thousands of loci leading to the generation of CUTs have been described in the yeast genome. Additionally, stable uncharacterized transcripts, or SUTs, have also been detected in cells and bear many similarities to CUTs but are not degraded through the same pathways.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

Plants depend on epigenetic processes for proper function. Epigenetics is defined as "the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence". The area of study examines protein interactions with DNA and its associated components, including histones and various other modifications such as methylation, which alter the rate or target of transcription. Epi-alleles and epi-mutants, much like their genetic counterparts, describe changes in phenotypes due to epigenetic mechanisms. Epigenetics in plants has attracted scientific enthusiasm because of its importance in agriculture.

Epigenetics of human development is the study of how epigenetics effects human development.

Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.

Epigenetics of autoimmune disorders is the role that epigenetics play in autoimmune diseases. Autoimmune disorders are a diverse class of diseases that share a common origin. These diseases originate when the immune system becomes dysregulated and mistakenly attacks healthy tissue rather than foreign invaders. These diseases are classified as either local or systemic based upon whether they affect a single body system or if they cause systemic damage.

Epigenetics of chronic pain is the study of how epigenetic modifications of genes affect the development and maintenance of chronic pain. Chromatin modifications have been found to affect neural function, such as synaptic plasticity and memory formation, which are important mechanisms of chronic pain. In 2019, 20% of adults dealt with chronic pain. Epigenetics can provide a new perspective on the biological mechanisms and potential treatments of chronic pain.

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