MJF College of Veterinary & Animal Science, Chomu (Jaipur) Department of Veterinary Biochemistry

Regulation of Gene Expression

Presented By- Dr. Mayank Kumar

Summary 1. DNA is the carrier of genetic information, and gene is the segment of a DNA molecule. The regulation of gene expression is absolutely essential for the growth, development and differentiation of an organism. A positive regulation increases gene expression while a negative regulation decreases. 2. The is the coordinated unit of gene expression. The of E. coli consists of regulatory genes and structural genes. The lac binds to the DNA and halts the process of of structural genes. The presence of lactose inactivates the repressor (derepression) leading to the expression of structural genes. 3. operon is regulated by a repressor. Tryptophan repressor binds to tryptophan, and then to trp operator gene to turn off the transcription. 4. Eukaryotic gene expression and its regulation are highly complex. Acetylation of leads to gene expression while deacetylation reverses the effect and methylation of DNA results in the inactivation of genes. Cont… 5. The -DNA interactions, brought out by motifs (helix-turn-helix, zinc finger, leucine zipper, helix-loop-helix), are involved in the control of gene expression. 6. Eukaryotic cells include gene amplification, gene rearrangement, and processing, transport and degradation of DNA to regulate gene expression. The bacterium contains about 4,400 genes present on a single . The genome of humans is more complex, with 23 pairs of (diploid) containing 6 billion base pairs of DNA, with an estimated 30,000–40,000 genes. At any given time, only a fraction of the genome is expressed. The living cells possess a remarkable property to adapt to changes in the environment by regulating the gene expression. Insulin is synthesized by specialized cells (beta) of pancreas and not by cells of other organs (kidney, liver), although the nuclei of all the cells of the body contain the insulin genes. Molecular regulatory mechanisms facilitate the expression of insulin gene in pancreas, while preventing its expression in other cells. Processes that affect the steady-state concentration of a protein

Fig.- Seven processes that affect the steady-state concentration of a protein. Each process has several potential points of regulation. Common patterns of regulation of transcription initiation Two types of negative regulation are illustrated- (a) Repressor (pink) binds to the operator in the absence of the molecular signal; the external signal causes dissociation of the repressor to permit transcription. (b) Repressor binds in the presence of the signal; the repressor dissociates and transcription ensues when the signal is removed. Positive regulation is mediated by gene activators. Again, two types are shown here- (c) Activator (green) binds in the absence of the molecular signal and transcription proceeds; when the signal is added, the activator dissociates and transcription is inhibited. (d) Activator binds in the presence of the signal; it dissociates only when the signal is removed. Note that “positive” and “negative” regulation refer to the type of regulatory protein involved: the bound protein either facilitates or inhibits transcription. In either case, addition of the molecular signal may increase or decrease transcription, depending on its effect on the regulatory protein. Types of Gene Regulation There are two types of gene regulation- 1. Positive regulation- The gene regulation is said to be positive when its expression is increased by a regulatory element (positive regulator). 2. Negative regulation- A decrease in the gene expression due to the presence of a regulatory element (negative regulator) is referred to as negative regulation. It may be noted here that double negative effect on gene regulation results in a positive phenomenon. Constitutive and Inducible Genes The genes are generally considered under two categories- 1. Constitutive genes : The products () of these genes are required all the time in a cell. So, the constitutive genes (or housekeeping genes) are expressed at more or less constant rate in almost all the cells and, further, they are not subjected to regulation e.g. the enzymes of citric acid cycle. 2. Inducible genes : The concentration of the proteins synthesized by inducible genes is regulated by various molecular signals. An increases the expression of these genes while a repressor decreases, e.g. the production of the enzyme β-galactosidase is induced (increased) by the presence of its substrate, lactose in the medium, tryptophan pyrrolase of liver is induced by tryptophan. The term pseudogenes is used to represent DNA sequences that have significant homology to a functional gene, but they cannot express due to mutations and these are non-functional, or significantly increase the size of the eukaryotic genome without any contribution to the expression of genes. One cistron-One subunit concept

The chemical product of a gene expression is a protein which may be an enzyme. It was originally believed that each gene codes for a specific enzyme, leading to the popular concept, one gene-one enzyme. This however, is not necessarily valid due to the fact that several enzymes (or proteins) are composed of two or more non-identical subunits (polypeptide chains). The cistron is the smallest unit of genetic expression. Cistron is the fragment of DNA coding for the subunit of a protein molecule (or a section of a DNA/RNA molecule that codes for a specific polypeptide in protein synthesis). The original concept of one gene-one enzyme is replaced by one cistron-one subunit. Models to study Gene Expression Elucidation of the regulation of gene expression in prokaryotes has well understood, the principles of the flow of information from genes to mRNA to synthesize specific proteins. The operon concept The operon is the coordinated unit of genetic expression in . The concept of operon was introduced by Jacob and Monod in 1961 (Nobel Prize 1965), based on their observations on the regulation of lactose metabolism in E. coli. This is known as lac operon. Bacteria have a simple general mechanism for coordinating the regulation of genes encoding products that participate in a set of related processes, these genes are clustered on the chromosome and are transcribed together. Many prokaryotic mRNAs are polycistronic- multiple genes on a single transcript and the single that initiates transcription of the cluster is the site of regulation for expression of all the genes in the cluster. The gene cluster and promoter, plus additional sequences that function together in regulation, are called an operon.

Fig.- Representative prokaryotic operon. Genes A, B, and C are transcribed on one polycistronic mRNA. Typical regulatory sequences include binding sites for proteins that either activate or repress transcription from the promoter. Lactose (lac) operon Operon is defined as a regulated gene cluster or in other words an operon is a group of coordinately regulated genes, the products of which typically catalyze a multienzyme metabolic pathway and their controlling elements. The purpose of lac operon is to provide the enzymes necessary to metabolize lactose (β-galactosidase and galactoside permease). The lac operon consists of a regulatory gene (I; I for inhibition), operator gene (O) and 3 structural genes (Z, Y, A). Besides these genes, there is a promoter site (P), next to the operator gene, where the enzyme RNA polymerase binds. The structural genes Z, Y and A respectively, code for the enzymes β- galactosidase, galactoside permease and thiogalactoside transacetylase. β- Galactosidase hydrolyses lactose (β-galactoside) to galactose and glucose while permease is responsible for the transport of lactose into the cell. The function of transacetylase is not known clearly yet.

Lac operon Modal

Fig.- Model of lactose operon in E.coli (A) Structure of lac operon (B) Repression of lac operon (C) Derepression of lac operon. (CAP—cAMP– catabolite gene activator protein bound to cAMP; RNAP– RNA polymerase). Metabolism of Lactose in Lac operon

Fig.- Lactose metabolism in E. coli. Uptake and metabolism of lactose require the activities of galactoside permease and β-galactosidase. Conversion of lactose to allolactose by transglycosylation is a minor reaction also catalyzed by β-galactosidase. Cont… The structural genes Z, Y and A transcribe into a single large mRNA with 3 independent translation units for the synthesis of 3 distinct enzymes. An mRNA coding for more than one protein is known as polycistronic mRNA. Prokaryotic organisms contain a large number of polycistronic mRNAs.

Repression of lac operon The regulatory gene (I) is constitutive. It is expressed at a constant rate leading to the synthesis of . Lac repressor is a tetrameric (4 subunits) regulatory protein (total mol. wt. 150,000) which specifically binds to the operator gene (O). This prevents the binding of the enzyme RNA polymerase to the promoter site (P), thereby blocking the transcription of structural genes (Z, Y and A). This is what happens in the absence of lactose in E. coli. The repressor molecule acts as a negative regulator of gene expression. Cont… Derepression of lac operon In the presence of lactose (inducer) in the medium, a small amount of it can enter the E. coli cells. The repressor molecules have a high affinity for lactose. The lactose molecules bind and induce a conformational change in the repressor. The result is that the repressor gets inactivated and, so, cannot bind to the operator gene (O). The RNA polymerase attaches to the DNA at the promoter site and transcription proceeds, leading to the formation of polycistronic mRNA (for genes Z, Y and A) and, finally, the 3 enzymes. Thus, lactose induces the synthesis of the 3 enzymes β-galactosidase, galactoside permease and galactoside transacetylase. Lactose acts by inactivating the repressor molecules, hence this process is known as derepression of lac operon. Gratuitous There are structural analogs of lactose (inducer) which can induce the lac operon but are not the substrates for the enzyme β-galactosidase. Such substances are known as gratuitous inducers. Allolactose, Isopropyl thiogalactoside (IPTG) is a gratuitous inducer. CAP (catabolite gene activator protein) or CRP (cAMP Receptor Protein) The cells of E. coli utilize glucose in preference to lactose; when both of them are present in the medium. After the depletion of glucose in the medium, utilization of lactose starts. This indicates that glucose somehow interferes with the induction of lac operon. For attachment of RNA polymerase to the promoter site catabolite gene activator protein (CAP) bound to cyclic AMP (cAMP) is necessary. The presence of glucose decreases the intracellular concentration of cAMP by inactivating the enzyme adenylyl cyclase responsible for the synthesis of cAMP. Due to the diminished levels of cAMP, the formation of CAP-cAMP complex is low. So, the binding of RNA polymerase to DNA (due to the absence of CAP-cAMP) and the transcription are almost negligible in the presence of glucose. Thus, glucose interferes with the expression of lac operon by depleting cAMP levels. Addition of exogenous cAMP is found to initiate the transcription of many inducible , including lac operon. Cont… So, it is clear that the presence of CAP-cAMP is essential for the transcription of structural genes of lac operon. Thus, CAP-cAMP acts as a positive regulator for the gene expression.

Fig.- Control of lac operon by catabolite gene activator protein (CAP) and the role of glucose Cont…

Fig.- Combined effects of glucose and lactose on expression of the lac operon. (a) High levels of transcription take place only when glucose concentrations are low (so cAMP levels are high and CRP-cAMP is bound) and lactose concentrations are high (so the Lac repressor is not bound). (b) Without bound activator (CRP-cAMP), the lac promoter is poorly transcribed even when lactose concentrations are high and the Lac repressor is not bound.

Tryptophan operon Tryptophan is an aromatic , and is required for the synthesis of all proteins that contain tryptophan. If tryptophan is not present in the medium in adequate quantity, the bacterial cell has to make it, as it is required for the growth of the bacteria. The tryptophan operon of E. coli contains- five structural genes (trpE, trpD, trpC, trpB, trpA), and the regulatory elements primary promoter (trpP), operator (trpO), attenuator (trpa), secondary internal promoter (TrpP2), and (trpt).

Leader Region of Try Operon Cont… The five structural genes of tryptophan operon code for three enzymes required for the synthesis of tryptophan from chorismate. The tryptophan repressor is always turned on, unless it is repressed by a specific molecule called . So, lac operon is inducible, whereas tryptophan operon is repressible. The tryptophan operon is said to be derepressed when it is actively transcribed. Tryptophan operon regulation by a repressor- Tryptophan acts as a corepressor to shut down the synthesis of enzymes from tryptophan operon. This is brought out in association with a specific protein, namely tryptophan repressor. Tryptophan repressor, a homodimer (contains two identical subunits) binds with two molecules of tryptophan, and then binds to the trp operator to turn off the transcription. Two polycistronic mRNAs are produced from tryptophan operon- one derived from all the five structural genes, and the other obtained from the last three genes. Besides acting as a corepressor to regulate tryptophan operon, tryptophan can inhibit the activity of the enzyme anthranilate synthetase. This is referred to as feedback inhibition and is brought out by binding of tryptophan at an allosteric site on anthranilate synthetase. Cont… Attenuator as the second control site for tryptophan operon- Attenuator gene (trpa) of tryptophan operon lies upstream of trpE gene. Attenuation is the second level of regulation of tryptophan operon. The attenuator region provides RNA polymerase which regulates transcription. In the presence of tryptophan, transcription is prematurely terminated at the end of attenuator region. In the absence of tryptophan, the attenuator region has no effect on transcription. So, the polycistronic mRNA of the five structural genes can be synthesized. Difference between Lac and Try operon

Lac operon Tryptophan operon (Try)

1. Inducible 1. Repressible

2. Catabolic System (Converts lactose into 2. Anabolic System (Synthesizes glucose) tryptophan)

3. Contain 3 Structural genes 3. Contain 5 Structural genes

4. Produce 3 inducible enzymes 4. Produce 5 repressible enzymes

5. Repressible protein is active 5. Repressible protein is inactive

6. High lactose turn transcription ON, in 6. High tryptophan turn transcription OFF. low glucose level

7. Lactose act as inducer 7. Tryptophan act as co-repressor. Cont…

Lac operon Tryptophan operon (Try)

8. Has 2 types of gene regulation- 8. Has single type of gene regulation- Negative & Positive Control Negative Control

9. Usually OFF, active under certain 9. Usually ON, inactive at high level of condition tryptophan

10. cAMP is necessary for CAP to switch 10. cAMP is not essential transcription ON

11. Turn on only in the presence of their 11. End product serves as a feedback substrate. inhibitor of the operon Cont… Cont… Differences between prokaryotes & eukaryotes with respect to transcription, translation and the spatial organisation of DNA The important are being as follows- (1) In eukaryotes only a single polypeptide chain can be translated from a mRNA (monocistronic). The operon found in prokaryotes are not exist in eukaryotes. (2) The DNA of eukaryotes is bound to and numerous basic protein which is lacking in prokaryotes. (3) In higher eukaryotes a large number of the base sequences in DNA is not translated. (4) Rearrangement & amplification of DNA segments is found in eukaryotes in a controlled manner. (5) In prokaryotes the regulatory sites are small, near to upstream from the promoters and binding of protein to such sites stimulates or inhibits binding of RNA polymerase. In eukaryotes, the regulatory regions are much larger. (6) In eukaryotes RNA synthesis takes place in the nucleus and transported to cytoplasm for translation, whereas such compartmentalization does not occur in prokaryotes.

Gene Expression in Eukaryotes Each cell of the higher organism contains the entire genome. As in prokaryotes, gene expression in eukaryotes is regulated to provide the appropriate response to biological needs. This may occur in the following ways- Expression of certain genes (housekeeping genes) in most of the cells. Activation of selected genes upon demand. Permanent inactivation of several genes in all but a few types. In case of prokaryotic cells, most of the DNA is organized into genes which can be transcribed. But, in mammals, very little of the total DNA is organized into genes and their associated regulatory sequences. Eukaryotic gene expression and its regulation are highly complex. Some of the important aspects are- Chromatin structure and gene expression- The DNA in higher organisms is extensively folded and packed to form protein- DNA complex called chromatin. The structural organization of DNA in the form of chromatin plays an important role in eukaryotic gene expression, because chromatin structure provides an additional level of control of gene expression. The genes that are transcribed within a particular cell are less condensed and more open in structure. Genes that are not transcribed which form highly condensed chromatin (heterochromatin). About 10% of the chromatin in a typical eukaryotic cell is in a more condensed form than the rest of the chromatin. This form, heterochromatin, is transcriptionally inactive. The remaining, less condensed chromatin is called euchromatin. Transcription of a eukaryotic gene is strongly repressed when its DNA is condensed within heterochromatin. Some, but not all, of the euchromatin is transcriptionally active.

A selected list of genes along with respective chromosomes Histone acetylation and deacetylation Histone acetylation & deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the are acetylated and deacetylated are essential parts of gene regulation. The nucleosome core particle consisting of H2A, H2B, H3 & H4 core histones, and DNA. These reaction are typically catalysed by enzymes with “ histone acetyltransferase” (HAT) or “” (HDAC) activity. Histones are acetylated by histone acetyl transferases (HATs), recently renamed lysine (K) acetyl transferases (KATs). Acetylation is the process where an acetyl functional group is transferred from one molecule to another. Deacetylation is simply the reverse reaction where an acetyl group is removed from a molecule. Acetylated histones, octameric proteins that organize chromatin into basic structural unit of the chromosomes. Acetylation removes the positive charge on the histones, thereby decreasing the interaction of the N termini of histones with the negatively charged phosphate group of DNA. Cont… As a consequence, the condensed chromatin is transformed into a more relaxed structure that is associated with greater levels of gene transcription. This relaxation can be reversed by deacetylation catalyzed by HDAC activity. Relaxed, transcriptionally active DNA is referred to as euchromatin. More condensed (tightly packed) DNA is referred to as heterochromatin. Condensation can be brought about by processes including deacetylation and methylation.

Methylation of DNA and inactivation of genes Cytosine in the sequence CG of DNA gets methylated to form 5′- methylcytosine. A major portion of CG sequences (about 20%) in human DNA exists in methylated form. In general, methylation leads to loss of transcriptional activity, and thus inactivation of genes. This occurs due to binding of methylcytosine binding proteins to methylated DNA. Methylated DNA is not exposed and bound to transcription factors and methylation of DNA correlates with deacetylation of histones.

Cont... Enhancers and tissue-specific gene expression Enhancers (or activators) are DNA elements that facilitate or enhance gene expression. The enhancers provide binding sites for specific proteins that regulate transcription. They facilitate binding of the transcription complex to promoter regions. Some of the enhancers possess the ability to promote transcription in a tissue-specific manner. Gene expression in lymphoid cells for the production immunoglobulins (Ig) is promoted by the associated with Ig genes between J and C regions. Transgenic animals are frequently used for the study of tissue-specific expression. The available evidence from various studies indicates that the tissue- specific gene expression is largely mediated through the involvement of enhancers. Some genes are referred to as silencers which diminish the transcription process. Combination of DNA elements and proteins in gene expression

Gene expression in mammals is a complicated process with several environmental stimuli on a single gene. The ultimate response of the gene which may be positive or negative is brought out by the association of DNA elements and proteins. In the illustrated Fig., Gene I is activated by a combination of activators 1, 2 and 3. Gene II is more effectively activated by the combined action of 1, 3 and 4. Activator 4 is not in direct contact with DNA, but it forms a bridge between activators 1 and 3, and activates gene II. As regards gene III, it gets inactivated by a combination of 1, 5 and 3. In this case, protein 5 interferes with the binding of protein 2 with the DNA, and inactivates the gene. Fig.- A diagrammatic representation of the association of DNA elements and proteins in gene regulation. A, B and C represent genes I, II and III (1…5 represent proteins) Motifs in proteins and gene expression A motif literally means a dominant element . Certain motifs in proteins mediate the binding of regulatory proteins (transcription factors) to DNA. The specific control of transcription occurs by the binding of regulatory proteins with high affinity to the correct regions of DNA. A great majority of specific protein-DNA interactions are brought out by four unique motifs—helix-turn-helix (HTH), zinc finger, leucine zipper, helix-loophelix (HLH). These amino acid motifs bind with high affinity to the specific site and low affinity to other parts of DNA. The motif-DNA interactions are maintained by hydrogen bonds and Van der Waals forces. 1. Helix-turn-helix motif The helix-turn-helix (HTH) motif is about 20 amino acids which represents a small part of a large protein. HTH is the domain part of the protein which specifically interacts with the DNA. Examples of helix-turn-helix motif proteins include lactose repressor, and cyclic AMP catabolite activator protein (CAP) of E. coli, and several developmentally important transcription factors in mammals. Cont…

Fig.- A diagrammatic representation of common motifs in proteins interacting with DNA. Cont… 2. Zinc finger motif The TFIIIA requires zinc for its activity. On analysis, it was revealed that each TFIIIA contains zinc ions as a repeating coordinated complex. This complex is formed by the closely spaced amino acids cysteine and cysteine, followed by a histidine- histidine pair. In some instances, His-His is replaced by a second Cys-Cys pair. The zinc fingers bind to the major groove of DNA, and lie on the face of the DNA. This binding makes a contact with 5 bp of DNA. The steroid hormone receptor transcription factors use zinc finger motifs to bind to DNA. 3. Leucine zipper motif The basic regions of leucine zipper (bZIP) proteins are rich is the amino acid leucine. There occurs a periodic repeat of leucine residues at every seventh position. This type of repeat structure allows two identical monomers or heterodimers to zip together and form a dimeric complex. This protein-protein complex associates and interacts with DNA. Good examples of leucine zipper proteins are the enhancer binding proteins (EBP)- fos and jun. 4. Helix-loop-helix motif Two amphipathic α-helical segments of proteins can form helix-loop-helix motif and bind to DNA. The dimeric form of the protein actually binds to DNA Gene Regulation in Eukaryotes The most important ones are briefly described here- 1. Gene amplification 2. Gene rearrangement 3. Processing of RNA 4. Alternate mRNA splicing 5. Transport of mRNA from nucleus to cytoplasm 6. Degradation of mRNA. Gene amplification In this mechanism, the expression of a gene is increased several fold. This is commonly observed during the developmental stages of eukaryotic organisms. For instance, in fruit fly (Drosophila), the amplification of genes coding for egg shell proteins is observed during the course of oogenesis. The amplification of the gene (DNA) can be observed under electron microscope. The gene amplification has also been reported in humen. Methotrexate is an anticancer drug which inhibits the enzyme dihydrofolate reductase. The malignant cells develop drug resistance to long term administration of methotrexate by amplifying the genes coding for dihydrofolate reductase. Cont…

Fig.- A diagrammatic representation of gene amplification (the genes are depicted in blue and red colours) Cont… Gene Rearrangment The human body has the capability to produce around 10 billion antigen-specific immunoglobulins. This is achieved by a process called gene rearrangement. It is explained on the basis of gene rearrangement or transposition of genes or somatic recombination of DNA. The structure of a typical immunoglobulin (Ig) molecule consists of two light (L) and two heavy (H) chains. Each one of these chains (L or H) contains an N-terminal variable (V) and C-terminal constant (C) regions. The V regions of immunoglobulins are responsible for the recognition of antigens. The phenomenon of gene rearrangement can be understood from the mechanism of the synthesis of light chains of Ig.

Fig.- A diagrammatic representation of gene rearrangement for the synthesis of light chain of immunoglobulin. Cont…

Processing of RNA The RNA synthesized in transcription undergoes modifications resulting in a functional RNA. The changes include intron-exon splicing, polyadenylation etc. Alternate mRNA splicing Eukaryotic cells are capable of carrying out alternate mRNA processing to control gene expression. Different mRNAs can be produced by alternate splicing which code for different proteins. Degradation of mRNA The expression of genes is indirectly influenced by the stability of mRNA. Certain hormones regulate the synthesis and degradation of some mRNAs. Estradiol prolongs the half- of vitellogenin mRNA from a few hours to about 200 hours. It appears that the ends of mRNA molecules determine the stability of mRNA. A typical eukaryotic mRNA has 5′-non-coding sequences (5′-NCS), a coding region and a 3′-NCS. All the mRNAs are capped at the 5′end, and most of them have a polyadenylate sequence (tailing) at the 3′end. Cont…

The 5′cap and poly (A) tail protect the mRNA against the attack by exonuclease. Stem-loop structures in NCS regions, and AU rich regions in the 3′NCS also provide stability to mRNA.

Fig.- A diagrammatic representation of a typical eukaryotic mRNA (NCS- Non-coding sequences) Why, Regulation of gene expression in eukaryotes is limited (1) The genome of eukaryotic cells is very much larger, containing several chromosomes and in somatic cells the genome is diploid. (2) The complex chromosomes are physically separated from ribosomes in cytoplasm by the perinuclear envelope. (3) Eukaryotic organism are capable of cell differentiation, whereas, prokaryotes lack this ability. (4) In highly differentiated eukaryotic cells of vertebrates, a large fraction of genome is permanently repressed, for example, a muscle cell cannot be transformed into a kidney cell, although each contains the structural gene characteristic of others. (5) Only a small fraction of the total genome of eukaryotic cells can be induced or derepressed reversibly. For all these above reasons, the molecular basis of the regulation of gene expression in eukaryotes is more complex than in prokaryotes.

Epigenetic regulation of gene expression The word is of Greek origin, means – over and above the genome. The term epigenetics is used to describe the changes in the characteristics of a cell or an organism that are not due to changes in the nucleotide sequence of the DNA (a change in phenotype without a change in genotype). Epigenetics regulates gene expression by modulating chromatin structure via histone modification or modification of DNA via methylation. The acetylation of histones leads to activation of gene expression, while DNA methylation & deacetylation is associated with a reduction in gene expression. The pattern of covalent modifications in histones that regulating gene expression is referred to as histone code. So, there is no change in DNA sequence, epigenetics is heritable due to coordination between histone modification and methylation of DNA. Epigenetic therapy of cancers

Hypermethylation of DNA in some parts of tumor suppressor genes is found in certain cancers. The enzyme DNA methyltransferase (DNMT) responsible for DNA methylation is targeted for cancer therapy. Many inhibitors of DNMT (E.g.- 5-azacytidine) have been approved by FDA, and are in use for the treatment of leukemia. Inhibitors of histone deacetylase (HDAC) are also employed in the epigenetic therapy cancers. HDAC inhibitors stimulate tumor suppressor gene expression by allowing acetylation of histones in chromatin structure. FDA has aproved the use of vorinostat for the treatment of T-cell lymphoma. Epigenetic therapy of cancer by employing various inhibitors (individually or in combination) holds a great promise.

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