Key findings:

Key findings of the abstract reveal the critical role of epigenetic modifications, specifically acetylation and deacetylation, in regulating gene transcription. This mechanism acts as a switch to control transcription activation and deactivation. Imbalance in acetylation can lead to various disorders including cancer, tumors, cardiovascular, and neurological diseases. HAT and HDAC inhibitors are being explored for therapeutic interventions.

What is known and what is new?
Epigenetic modifications, namely acetylation and deacetylation, regulate gene transcription by activating or deactivating it, functioning as a transcriptional switch. Imbalances in these processes contribute to disorders like cancer and neurological diseases. HAT and HDAC inhibitors show promise in clinical research and medication development for managing epigenetic-related diseases.

What is the implication, and what should change now?
The abstract underscores the critical role of epigenetic modifications in gene regulation, highlighting the potential therapeutic targets of HAT and HDAC inhibitors for various diseases. Future research should focus on elucidating precise mechanisms of epigenetic dysregulation and developing targeted therapies to address specific disorders effectively.
 

In a eukaryotic cell, the length of the DNA molecule is approx. 1m (approx.6ft). In the nucleus, DNA is organized in  a hierarchical order with the help of proteins collaborating to create a structure called chromatin. The Major The  nucleosome is a kind of chromatin unit made up of DNA and histone protein. Histone protein gives structural support to  a chromosome [1].  Histone protein, lapping around the DNA, is an octamer whose  modification by acetylation after translation leads to activation of the transcription process regulated by the enzyme histone  acetyltransferase (HAT) [2]. Acetylation occurs in the lysine residues of N-terminal tails of histones.  HAT transfers the acetyl group present in the acetyl-CoA to the lysine residue containing the ɛ-NH3+ group at the N terminal tails [3]. Due to acetylation, the interaction between DNA and histone protein varies. The reverse process of acetylation is deacetylation which is catalyzed by the enzyme HDAC. The  mechanism of HDAC is either NAD+ dependent or NAD+ independent [4]. HDAC removes the  acetyl group from the lysine residue which recondenses the DNA. NAD+-dependent HDAC can be classified into three  classes according to their similarity to the yeast proteins RPD3 (class 1), HDAC1 (class 2) and SIRT2 (class 4) whereas  Zn-dependent HDAC is HDAC11 [5]. Due to this acetylation-deacetylation process in histone  modification, the proliferation and cell differentiation occur which causes various kinds of diseases such as several types  of tumours, prostate cancer, colon cancer, breast cancer, skin cancer, cardiological disease, neurological diseases,  vascular disease, genetic disorders related disease Rubinstein-Taybi Syndrome, Fragile X syndrome and it also influences  the metabolism process [6-12]. HDAC inhibitors and HAT  inhibitors play an important role in the treatment of diseases caused by histone modifications [12-13]. 

In this review, we have discussed the histone protein and its role in DNA binding. Then the purpose of the epigenetic  modification and its result will also be explained. The process of epigenetic modification, acetylation and deacetylation,  and the enzymes involved in this process are HAT and HDAC respectively will be covered in more detail. Then we’ll focus on  the diseases associated with epigenetic modification. After that, the classes of inhibitors, their activity and their uses in  the current clinical research for drug development will be discussed. 
 

Histone has four types- H2A, H2B, H3, H4. These all  subunits are single monomers, but these subunits are  joined twice to create an octameric core with 146-147  base pairs of DNA firmly wrapped around it. The  variable length of linker DNA separates nucleosome cores, which are linked by the linker histone H1  [1]. 

DNA replication and gene expression both are  controlled by the overall structure of chromatin and its  domains. Variable length of N-terminal tails and histone  domains are present in core histones. These N-terminal  tails are abundant in lysine and arginine and all the  modifications like acetylation may occur in the side  chain of lysine, the peptide bond or peptide backbone  modification does not take place [14]. The N tail plays a vital role in extensive post-translational  modifications (PTMs), such as acetylation and  phosphorylation. Acetylation of histone protein has  been controlled by the transcription, whereas  acetylation of histone is associated with silencing.  PTMs are also implicated in chromatin assembly and  DNA replication. PTMs consist of the  epigenome which comprises changes to DNA that are  connected to proteins. These epigenetic modifications  are switches for the regulation of gene expression and  are chemical modifications of the DNA and histones  that do not change the DNA sequence. Changing the  chromatin structure is correlated with the  phosphorylation of linker histone [15]. 

 
As a result, several recent studies contend that  histones play an important role in the control of  biological processes such as transcription. It is more  essential than understanding histone biology on a  structural basis. 
 

A 7 resolution crystallographic study with a  (H3)2(H4)2 tetramer yielded the structure of the  nucleosome core particle, with two H2A H2B dimers at  the centre and DNA wrapped around it. [1]. The histone fold domain is  found in each core histone protein, which is made up of  three -helices linked by two loops. The handshake motif  allows for heterodimeric connections between core  histones. Each of the core histones has an N-terminal  tail that binds to a wide range of PTMs. In general, the  main histone protein genes are found in gene clusters  that are largely expressed during the S phase of the cell  cycle. These histones are involved in the packaging of  freshly produced DNA. Some histone variations are  expressed throughout the cell cycle and are not limited  to the S phase of the cell cycle [16]. Now we will study the structure of  subunits of histone proteins. 

i) Histone H2A: - The core histone is H2A which has  the largest number of variants. H2AZ and H2AX are  
the variants of histone H2A, mainly found in most  eukaryotes. Histone H2A is characterized by its genome  localization and its divergent C-terminal sequences.  H2AZ has been involved in transcriptional activation in  yeast and preventing the spread of silent  heterochromatin. H2AX histone variants are  distinguished by a C-terminal extension containing the  consensus SQ[E/D] sequence, which denotes a  hydrophobic amino acid [1]. 

ii) Histone H2B: - H2B histone variations are rare, yet  they play important roles in chromatin compaction  during gametogenesis. Furthermore, H2B variations  have been discovered in male gametic cells from lilies  and, more recently, in bovine and human spermatozoa,  albeit their particular functions remain unknown. 

iii) Histone H3: - H3.3, CenH3, and H3.4 are the  components of the histone H3 variations. The H3.3 variant  is present in transcriptionally active chromatin and is  not S-phase regulated. The H3.4 component is only  found in the testis. H3 histone variations are detected in  primordial spermatocytes. CenH3 variants are located  in centromeric chromatin, and their N-terminal tails are  divergent, with little sequence resemblance to  conventional CenH3. [1]. 

iv) Histone H4: - The most conserved histone is the  histone H4 variation. In the nucleosome core particle,  H4 histone interacts with the other three core histone  proteins. There are even identical sequence variations  that are expressed separately within a cell cycle, as  contrast to the main synthesis period for histones in the  S phase [17].

Allfrey et.al.[18] first reported histone acetylation in  1964 [19]. It occurs in the nucleus of the  eukaryotic cells which is regulating gene transcription  and expression, so it is an epigenetic modification.  Basically, DNA wraps tightly to histone proteins, to lose this bind from histone acetylation take place  because if DNA does not get free from protein, then it  can’t further proceed towards gene regulation. The  enzymes that help the acetylation process are known as  histone acetyltransferases (HATs). Mainly the enzyme HATs acetylated lysine amino group from acetyl-CoA to form ε-N acetyl-lysine [20]. Histone is a positively charged protein and DNA is negatively charged, that’s why their interaction is so strong and tight.  Here acetylation removes the positive charge from histone protein, and it becomes negative. Acetylation reduces the affinity of the histone for DNA, so their interaction decreases, and DNA loses its coiling pattern, as a result, the transcription process is activated.  Acetylation is an activator of transcription. Acetylation is a reversible process, so histone deacetylases (HDACs) are the enzymes that counteract that activity.
 

Those proteins which remain in chromatin after removing the histone proteins are known as non-histone  proteins. A large group of heterogeneous non-histone proteins plays a role in the compaction and organization of higher-order chromosome structure, they are also involved in nucleosome remodeling, DNA replication,  RNA synthesis and processing, nuclear transport,  steroid hormone activity, and the transition from  interphase to mitosis. Proteins that are not histones, such as scaffold protein, DNA polymerase, heterochromatin protein1, and polycomb are very common. This non-histone protein is acidic in nature  [21]. 
 

A group of enzymes that transfers acetyl group from acetyl coA to lysine sidechain containing epsilon amino group is known as HAT. Depending upon the mechanism of catalysis HATs can be classified into two classes such as HAT A localised in nucleus, takes part in transferring acetyl group from acetyl coA to lysine  on histone & HAT B localised in cytoplasm, takes part  in transferring acetyl group from acetyl coA to lysine  residue on newly synthesised free histone [2] [22]. 
 

Based on subcellular localization HATs are classified into two classes, one type A HATs and another one is type B HATs [23]. In the nucleus, type A HATs are found that are involved in the regulation of gene expression through acetylation. Based on their homology and acetylation mechanism the type A HATs are further classified. PCAF, Gnc5, and ELP3 are members of the GNAT family. The CBP/p300 family members are CBP and p300. Tip60, MOZ, MORF, HBO1, and HMOF all are members of the MYST family. TAF1 and TIFIIIC90 are transcriptional factor-related HAT families. In HATs, p600, SRC1, CLOCK, and AIB1/ACTR/SCR3, etc, several steroid receptor coactivators are included. In the cytoplasm, type B HATs are found that are responsible for acetylating the newly synthesized histones to their assembly into nucleosomes. HAT1 is an example of type B HAT members and their contribution to DNA repair and histone deposition [20]. 
 

The GANT family, Gcn5-related N acetyltransferases, is characterized by the presence of  bromodomain and is located in the lysine residues on  histones H2B, H3, and H4. The GNAT family members  are marked by up to four conserved motifs (A-D)  located in the catalytic HAT domain. The GNAT  family comprises the most highly conserved motif A,  and the sequence is Arg/Gln-X-X-Gly-X-Gly/Ala,  which is important for the recognition and binding of acetyl-CoA [24]. In GNATs  motif C was also found, but the majority of other  known HATs are not present. The Gcn5 HAT is one of  the best-characterized members in yeast. It includes four functional domains: N-terminal domain, c-terminal  bromodomain, an Ada2 interaction domain, and a  highly conserved catalytic (HAT) domain. In  mammalian GNATs, the PCAF (p300/CBP-associated  factor) and GCN5 are sharing a homology throughout  their sequences.

The N-terminal region of these proteins contain 400 residues which are absent in yeast Gcn5, but their HAT  functions are preserved. The first HAT protein was Hat1 that is responsible for the cytoplasmic HAT  activity in yeast and also binds strongly to histone H4.  The example of type A HAT found in yeast is Elp3,which is part of the RNA polymerase II  holoenzyme and plays an important role in the  elongation of transcription [24]. 
 

Based on Four members MOZ, Ybf2 (Sas3), Sas2, and Tip60, the MYST family of HATs has been  named. Esa1, MOF, MORF, and HBO1 are other important members. The presence of zinc  fingers and chromodomains help to characterize these  HATs families, which are located in the acetylated  lysine residues on histones H2A, H3, and H4. Several MYST family proteins have highly preserved motif A, which  are important for acetyl-CoA binding. The N terminus region of the HAT domain of MYST proteins rich in  cysteine is involved in zinc binding that is necessary for  HAT activity. The first human MYST family member  was Tip60 (Tat interactive protein, 60kDa) exhibiting HAT  activity. A homolog of MOZ (monocytic leukemia zinc  finger protein) is Sas3 located in yeast,  an oncogene located in humans. Esa1 was the first  necessary HATs found in yeast. The HAT activity is very important for the transcription of the male X  chromosome in flies. HBO1 (HAT bound to ORC1) was the first HAT Human, associated with the  replication complex origin. MORF, which are MOZ related factors, shows close homology to MOZ  throughout the entire length [3].

Histone acetylation and deacetylation are necessary for regulation of genes. The acetylation was maintained by different specific promoters such as HATs and HDACs; exploring their performance over large  chromosomal domains denote that the acetylation state  is in a continuous genome-wide flux. Histone acetylation and deacetylation regulate the transcription process by manipulating the higher-order folding  properties of the chromatin fiber. Chromatin structure is not merely altered by acetylation of lysine residues but  also gives unique binding surfaces for repressors and  transcription activators. Histone acetylation and regulation of transcription connect to similar molecular.

mechanism in yeast and multicellular eukaryotes but  show a different ratio in between restrictive chromatin  and permissive [24].T The role of  histone acetylation in regulating gene expression is the  main point. Acetylation of histone protein changes the  nucleosome structure, or it provides a protein binding  signal. According to the changes in the nucleosomes  structure, an acetyl group is added to the lysine ε-amino  groups of N-terminal tails and neutralizes the positive  charge of the lysine side chain. This modification may  affect the interaction between DNA and the lysine  residue and contact becomes weaker with the negatively  charged DNA backbone. According to the histone  acetylation, it provides a signal for protein binding and an added acetyl group to create a new surface for protein  association. Docking sites are created by lysine  acetylation for a protein molecule which is called  bromodomain. 

This bromodomain is located in the transcription and chromatin regulators. Different species carry different  numbers like in humans there are more than 60  bromodomain proteins, in Drosophila the number is 16  and in Saccharomyces cerevisiae 10 Bromo proteins  present. But all bromodomains can’t recognize acetyl lysine. It is reported that bromodomain containing protein, p300 binds to histone in acetylation. Chromatin acetylation by HATs is the function of bromodomain in gene regulation. In S. cerevisiae Gcn5 HAT bromodomain is needed for the SAGA complex to associate with nucleosome remodeling and acetylated chromatin. Gcn5 bromodomain identifies Lys16- acetylated [24]. 

Another important yeast protein, Bdf1 has targeted  the H4 histone tail. That protein has been needed for  anchoring TFIID to the PHO5 promoter of S.  cerevisiae, when the nucleosome relocates altered  TATA which is H4 acetylation dependent. 
Another important yeast protein, Bdf1 has targeted  the H4 histone tail. That protein has been needed for  anchoring TFIID to the PHO5 promoter of S.  cerevisiae, when the nucleosome relocates altered  TATA which is H4 acetylation dependent. 
Bromodomain containing acetylated histone proteins was recently established in the living cells by  FRET analysis. The regulator of transcription Brd2 connected with the acetylated lys12 of H4 and to a  lesser degree with H2B but not with H2A and H4.  Conversely, TFII250 is a component of TFIID, and was found to recognize H4 and H3 that is of the lesser extent with H2B not H2A. PCAF, the third bromodomain  containing protein, was analyzed and produced signals of  FRET with H4 and H3, not H2A or H2B. 
 

Figure 1: Histone modification due to acetylation/deacetylation 

Acetylation is a sort of epigenetic remodelling. of chromatin by which histone protein tightly wrapped  around DNA is acetylated and relaxed. Due to this acetylation, the DNA becomes accessible for  transcription factors, co-factors, RNA polymerase II &  transcription proceeds. This acetylation is catalysed by the enzyme HAT. Another enzyme called HDAC counteracts the activity of HAT by removing the acetyl group from the core histone protein. The transition state of the substrate is stabilized by tyrosine, a histone residue that encourages the acetyl group to be released from  histone lysine [25]. This is known as deacetylation & it reforms the compact structure of chromatin. In eukaryotes, HDACs can regulate transcription as well as gene expression by acetylation  and deacetylation of the lysine residue of the histone  proteins’ N-terminal domain. [3]. 
 

HDACs are classified into four categories based on  their resemblance to yeast proteins: 
Class I: HDAC1, HDAC2, HDAC3 and HDAC8 Class II: (IIa) HDAC4, HDAC5, HDAC7, HDAC9 and  (IIb) HDAC6, HDAC10 
Class III: SIRT1 to 7 
Class IV: HDAC1.

Class I shows similarity to yeast RPD3, class II  shows similarity to yeast HDAC1, class III shows  similarity to yeast SIR2 & Class IV has features of  sophistication class I & II HDACs [26-27]. Class I is found within the nucleus  near the N-terminal portion. For HDAC1 the nuclear localized sequence is encoded by the C-terminal located  sequence KAKKAR KT and it must transfer to the  nucleus [25]. Class II cells can  traverse between the cytoplasm and the nucleus by  phosphorylation suggesting the involvement of HDAC  in non-histone protein acetylation. HDACs are actively engaged in deacetylation using two mechanisms  depending on which they can be classified into two  families: Zn+ dependent HDACs & NAD+ dependent  HDACs. In Zn+ dependent pathway, the acetylated substrate present within the catalytic centre of the  enzyme is stabilized by the Zn+ ion, and the carbonyl  group in acetyl becomes polarized which facilitates the  water molecule's nucleophilic interaction to the carbon  atom and this is sensitive to TSA, SAHA. On the other hand, in NAD+ dependent pathway due to the transfer  of acetyl group, nicotinamide and O-acetyl ADP ribose  is formed and this is insensitive to TSA. [8] [13]. 
 

Class I HDACs in the nucleus may deacetylate all  four subunits of histones, permitting transcription to  proceed on the genome. The specificity of histone substrate for HDACs is quite difficult to be said  because for two main reasons: Class I HDACs have the  ability to deacetylate several lysine residues and the  majority of Lysine residues can be deacetylated by  multiple class I HDACs. Some nonhistone proteins such as p53, E2F1, the corepressor YY1, Proliferating Cell  Nuclear Antigen (PCNA), and lysine demethylase1 are  transcription factors due to the nuclear localization of  HDAC1. These proteins show different effects on  deacetylation such as p53 destabilized, E2F1  inactivated, YY1's repressive impact is decreased, as is  PCNA's capability to bind to DNA polymerases beta  and delta reduced, the ability of LSD1 to bind histone  H3 enhanced. ERRα was shown to be deacetylated by  HDAC8. As a result of this, the function of transcription factors is enhanced and the deacetylation  of cohesin complex SMC3 encourages cohesin  resynthesis after it has been removed from chromatin  during anaphase or prophase. Class I HDACs also catalysed the post-translational modification by  removing the acetyl group from the histone tail of H3 &  H4.  

In many multiprotein complexes, HDAC1 & HDAC2 are found together but in recent studies of  humans and mice, it has been shown that HDAC2 can  function independently from HDAC1 in vivo. The Myc,  a transcriptional activator, and Mad, a transcriptional  repressor, are both involved in the heterodimeric  binding partner Max which is also a transcription factor.  

The DNA sequence containing the same E box binds to both Myc-Max and Mad-Max complexes but the  HDAC1 and HDAC2 are required for mSin3 scaffold  protein to be associated with the Mad-Max complex.  Some co-repressor such as SMRT and N-CoR bind to HDAC3 effectively and this requirement of HDAC3 to promoters prevents the transcription. HDAC1 is required for repression of E2F-mediated transcription by Rb and this requirement leads to the decrease of  acetylation at E2F-regulated promoter [27]. HDAC6 controls polyubiquitin-chain turnover and permits ubiquitylated proteins to be recognised and transported by binding its zinc-finger domain with  ubiquitin. HDACs may be targeted to specific chromatin domains by noncoding RNA (ncRNA) [28]. Each protein has at least one catalytic domain where acetyl can bind and the localization of  this domain is conserved within each class. The catalytic domain for the members of class I and class IV  occupies most of the protein sequence. But the catalytic  domain of class IIa HDACs always occupies the C terminus of the protein sequence [25]. Class III HDAC SIRT2 prefers to deacetylate  H4-K16 histone protein during the G2/M transition of  cell cycle and it also influences the timing of S-phase  entry [27].  

A specific serine residue is phosphorylated which  induces nuclear export of HDACs of class IIa and this  triggers the 14-3-3 protein binding. This interaction can  mask the NLS or unmask the NES. The short histidine  residues which cannot reach the active site replace the  catalytic Tyrosine 345 residue. This replacement of  class IIa HDACs triggers the deacetylation of the  acetylated histone without disturbing the transcriptional  repression. Transcription factor RUNX2 is shown to be  deacetylated by HDAC4. HDAC6 has two C-terminal  zinc finger domains known as CD1 and CD2 which  have a higher tendency for binding with free ubiquitin.  It was shown that the CD1 prefers to deacetylate the C terminal of the acetyl-lysine substrate whereas CD2 is  effective on any acetyl-lysine substrate α-tubulin is  deacetylated by HDAC6 which stabilizes the  microtubules. Experiment has shown that the MSH2 is  deacetylated and then ubiquitinated by HDAC6 which  decreases its stability. HDAC11 can strongly show its  activity for lysine defatty-acylation than deacetylation.  It also deacetylates SHMT2 which influences the  ubiquitination and degradation of the proteasome of the  IFN receptor [25].  

HDAC can also deacetylate non-histone proteins, consequently modulating gene expression. HDAC1 from class I and SIRT1 from class III can deacetylate  the tumour suppressor p53, HDAC3 from class I can  deacetylate the p65 subunit of NF-kB which triggers its  association with IkBa and leads to nuclear exportation  of NF-kB. SIRT1 deacetylates the transcription factor p73 and SIRT3 deacetylates Ku70. This kind of deacetylation by HDAC can directly show effects on various physiologic processes, including inflammation,  apoptosis, autophagy, metabolism, and differentiation  [8]. Nonhistone proteins can be  also affected by the HDAC present in the p300 which is  a multiprotein complex [22]. 

HDACs have many other roles such as in metabolic  processes, DNA metabolism by taking the acetyl group  off of histone as well as nonhistone proteins. Some of  the HDACs also play an important role in the replication  of DNA, genomic stability, and the response to DNA  damage for their pathogenic deregulation. Also in  virology, it plays an important role. Experimentally it  has shown that the human HDAC2 is the sole viral  Non-structural protein 5 (NSP5) interactor in HEK293T  cells SARS-CoV-2, which is responsible for the  COVID-19 pandemic [25].  
 

Improper acetylation of a transcription factor may  provoke diseases by imbalanced enzyme activities. The  CBP/p300 HAT family is vital for differentiation, cell  proliferation, apoptosis, and transformation. The  occurrence of human chromosomal translocations  further highlighted the CBP family of HATs, which fuse CBP to MOZ (monocytic leukaemia zinc-finger  protein), or MLL (mixed-lineage leukaemia). In humans  these translocations can lead to leukaemia. In humans  the p300 plays a tumour-suppressor role, and has been  investigated as well. Spontaneously arising mutations in  the p300 gene have been a reason for various human  cancers, as a result, two primary tumours and a number  of cancer cell lines. In the human CBP gene mutations  were related to Rubinstein-Taybi syndrome (RTS)  [29] mental retardation, craniofacial defects,  big toes, and broad thumbs are the reason for a  developmental haploinsufficiency disorder. This disease  is very common in humans, an average of 1 of 300  patients are suffering from mental retardation disease  [12].  

The imbalance of PCAF can stop growth. This is  mainly happening due to the imbalanced interaction of  PCAF and two important regulators of the cell cycle  and these are E2F and p53. The PCAF indicates first the  tumour suppression that comes from viral infection. 

Tip60 also can relate with the interleukin-9 receptor  and membrane receptor, and as a result, it is a reason  for asthma and T cell oncogenesis [12]. 
The relation between the MOZ protein (monocytic  leukaemia zinc finger protein) and cancer is better  established. In leukaemia, several types of  translocations have been observed. All fusions of  different HATs are associated and interact with two  different HATs domains. So, this can postulate that the  misdirection of HATs activity, either of the MOZ, the TIF2, or the CBP/p300 moiety is the reason for the  malignant conversion type of leukemia [30]. 
 

When deacetylation occurs in the normally active  region and hyperacetylation occurs in the normal  silence region, several diseases can develop. The  activity of HAT/HDAC should be regulated, otherwise,  dysregulation occurs that leads to various kinds of  tumours, cancers, metabolic disorders, neurological  disorders, and also the cardiological problem [12]. 

(i) Cancer:  
A set of key genes which influence the growth of the cancer cells and play an important role in their  survival are strongly maintained by the HDACs. After knocking out the different HDACs (each was a member of class I HDAC) from individual mice, the importance of HDACs in gene regulation was observed.  The observation shows that the mice in which the HDAC1 was absent, died before birth due to  proliferation defects. The mice in which HDAC2 was absent, died on the first day after birth due to cardiac  malformation. The mice in which the HDAC3 was  absent, died before birth due to gastrulation. According to the types of tumours, the levels of HDAC are varied  in different types of cancer cells such as HDAC1 are  present in prostate, lung, esophageal, colon and breast  cancer cells; HDAC2 are present in colorectal, cervical  and gastric cancer cells; HDAC3 is expressed in colon  and breast tumour cells; HDAC6 are present in  mammary tumour cells; HDAC8 is present in  neuroblastoma cells and HDAC11 is expressed in  rhabdomyosarcoma. Histone H4 hypoacetylation at  lysine 16 linked with multiprotein complexes was  highlighted as an epigenetic signature in cancer cells.  The functions of some proteins which are most  important in cancer (tumour protein p53, α3 subunit  RUNX3, STAT3, β-catenin, estrogen receptor, EKLF,  Myc, MyoD, NF-kB, HIF-1α, GATA family), are  modulated by HDACs [13] [27] [28]. Acute myeloid  leukaemia and urothelial are observed for low  expression of HDAC5 but it can cause breast cancer  with high expression. Renal cancer, non-small cell lung  cancer, thyroid cancer is caused by the upregulation of  HDAC9. Lung cancer and gastric cancer are caused by  the low regulation of HDAC10 [25]. Due to the acetylation/deacetylation mechanism  of many DNA repair proteins, the pathogenesis of  tumours was elucidated which helps to discover the new  drugs for post-translational modification for the  treatment of cancer [26]. It is published in  a recent study that tumour suppression can be influenced  by PIB5PA and its downregulation was also observed in  melanoma. HDACs can cause histone hypoacetylation  which leads to the downregulation of PIB5PA and  decreases the survival of melanoma cells [10]. The inflammatory response is increase

in an in vivo allergic inflammatory response model by  HDAC1 and the parenchymal lung inflammation can  also increase for HDAC1 deficiency in the Th2-type  asthma model of mice [8]. 

(ii) Neurological disease: 
Epigenetic changes that occur due to deacetylation  by HDAC class I proteins are associated with  neurological disease. It was observed from an  experiment that the variation of Histone acetylation  levels as a result of psychostimulant interaction are  affected by HDACs [31]. Critical  defects in brain development have been shown due to  the deficiency of HDAC4. HDAC9 appears to be  important for mature neuron function and deregulation  of this can cause defects in brain cells [25]. Huntington's and Alzheimer's are two  neurological diseases caused by the imbalance between  histone acetylation and deacetylation [32] [33]. 

(iii) Heart disease:  
The deletion of HDAC3 in the heart causes  interstitial fibrosis. In the T-cells in the interchange  between intestinal lymphocytes and intestinal epithelial  cells, the role of HDAC3 has also been observed. A loss  of cardiac function has been shown after stress in  HDAC5-null mice due to an increase in cardiac  hypertrophy [25]. In heart failure,  HDACs have been discovered to interact with the  transcription factor Mef2 and control gene expression [7].

 
(iv) Vascular disease:  
The epigenetic modification of chromatin has a role  in vascular diseases such as Vascular restenosis,  atherosclerosis. Studies have indicated that HDAC  activity can impact angiogenesis as a result of hypoxia,  shear stress and VEGF-induced stem cell  differentiation. It is evident that the HDAC7-null cell is  involved in the development of normal vascular and in  embryonic lethality [6].

or acetylation pattern change are both connected in inflammatory diseases and restoring the  balance between acetylation and deacetylation will  benefit those patients. Reduction of acetylation is caused by HAT inhibitors. In the end, it leads to the responses of the different functions of HATs.  Therefore, it is critical to identify which HATs are associated with inflammatory disorders and which require targeted to restore equilibrium. In viral diseases, HAT inhibitors can be used to treat patients. HATs enhance viral replication and viral protein invasion.  HATs bind to viral proteins. E1A or Tat. It might be a  promising target for inhibitor research. HATs play a crucial part in the control of transcription in Alzheimer's  and Huntington's disease; however, it has been  established that this is an excellent target for HAT  inhibitors [36]. 

HAT subtypes have large differences in function but similarities in the structure that might be vital in preventing side effects. Already, inhibitors are developed between selective HAT families, although  selectivity of different functions and similar structures  are very challenging. Generally, the natural products of  HATs inhibitors are nonselective and inhibit a target  besides HATs, including antioxidant activity, or protein  reactivity. Some natural by-products have been  developed between these selective HAT families  [23]. 

The potential of Allosteric inhibitors to be selective between subtypes of the same family, because of the  variation of N- and C-terminal regions, but the catalytic  domain is identical for HATs families. These inhibitors are shown to exhibit biological effects, although in vitro it is still limited. HATs are correlated with various proteins, modulating their activity but sometimes acetylation activity is not needed, like bromo domains or other  protein interaction domains. Protein–protein interactions inhibition is the way of targeting specific HEAT pathways [23]. 

Figure 2: Regulation of transcription by histone acetylation 

HDAC inhibitors are the types of compounds that play the opposite role of HDAC i.e., these proteins inhibit the deacetylation activity of HDACs. Due to its activity, it has a lot of therapeutic roles as well as it also helps in gene regulation. Sometimes even after  preventing the condensation of the chromatin structure  by inhibiting deacetylation, HDAC inhibitor does not  always increase the transcription as this can have an  impact on the function of transcription factors in both  beneficial and negative ways. 
 

Based on their chemical structure, HDAC inhibitors may be classified into five types: (i) hydroxamates, (ii)  short-chain fatty acids, (iii) benzamides, (iv) cyclic  tetrapeptides and (v) sirtuin inhibitors. Based on their activity on HDAC, HDAC inhibitors can also be divided into two classes: HDAC specific inhibitors and  HDAC-pan inhibitors.

(i) Hydroxamates: Trichostatin A (HDAC-pan), SAHA  (HDAC-pan), Belinostat (HDAC-pan), Panabiostat  (HDAC-pan), Givinostat (HDAC-pan), Resminostat  (HDAC-pan), Abexinostat (HDAC-pan), Quisinostat  (HDAC-pan), Rocilinostat (HDAC-II specific),  Practinostat (HDAC-I, II, IV specific), CHR-3996  (HDAC-I specific). 

(ii) Short-chain fatty acids: Valproic acid (HDAC-I, IIa  specific), Butyric acid (HDAC-I, II specific),  Phenylbutyric acid (HDAC-I, II specific). 

(iii) Benzamides: Entinostat (HDAC-I specific),  Tacedinaline (HDAC-I specific), Mocetinostat (HDAC I, IV specific). 

(iv) Cyclic tetrapeptides: Romidepsin (HDAC-I  specific). 

HDAC-mediated repression of genes can cause uncontrolled cell growth. HDACs repress the transcription of  (1) cyclin-dependent kinase inhibitors (CDKI), allowing continued proliferation; (2) differentiation factors, allowing  proliferation instead of differentiation; and proapoptotic factors, permitting survival. (b) HDAC inhibitors (HDACi) can  restore appropriate gene expression, preventing the uncontrolled growth of the cell. HDAC, histone deacetylases [27] (v) Sirtuins inhibitors: Nicotinamide (all Class III HDAC specific), Sirtinol (SIRT1, SIRT2 specific),  Cambinol (SIRT1, SIRT2 specific), EX-527 (SIRT1, SIRT2 specific) [25] [13]. (figure 3)

The different inhibitors can show a different anticancer effect on the different types of cancer. VPA  can show its activity in bladder cancer but not in  prostate cancer [13]. HDAC  inhibitors of hydroxamic acid (hydroxamate) groups can  be specific as well as nonspecific. The activity in  inhibition of HDAC enzyme depends on the ability of  hydroxamic acid to form a chelate complex with Zn+  cation in the active site of enzyme HDAC. Pan-HDAC TSA inhibitor was used to treat hepatocarcinoma  HepG2 cells. and the acetylation status of histone  H3/H4 was observed. After observation, it was seen that  the hyperacetylation of the TSS region appeared as transient but the TSS region downregulated by the TSA  inhibitor showed a strong reduction in acetylation over  time [25].  

Butyrate is a nonspecific HDAC inhibitor that has  many biological effects such as cell cycle arrest, growth  suppression, etc. The link between histone deacetylation  and cell-static effect is strengthened by HDAC  inhibitor Trichostatin A which induces differentiation  [28]. It can also reduce cardiomyocyte  hypertrophy and as a result of this, the non-muscle cells  within the heart are affected which causes various  inflammatory responses linked with toxicity. FDA approved the use of vorinostat and romidepsin HDAC inhibitors for the treatment of cutaneous T-cell  lymphoma. HDAC inhibitors can also be used for the  treatment of chronic arthritis and heart failure [7]. Romidepsin has its role in clinical  treatment in which the cells in G2/M transition are  blocked by increasing the tumour suppressor p19, p21  and p27 [25]. HDAC inhibitor  SAHA plays a crucial role in the treatment of breast cancer, colon cancer, chronic lymphocytic leukaemia by  inducing autophagy which again regulates the  degradation of p53 mutant, further influencing the  survival of cancer cells. It also increases the  radiosensitivity by targeting RAD51 and use for the  treatment of pancreatic cancer. Some HDAC inhibitors  such as rocilinostat, tubacin, tubastatin A etc are  HDAC6 specific. HDAC6-specific inhibitors can block  the function of the domain present in HDAC6 and due  to this ability, it plays an important role in bladder cancer,  malignant melanoma, etc. Assisting the acetylation of  α-tubulin by inhibiting HDAC6, they can regulate  cancer cell cycle and apoptosis [34].  HDAC inhibitors can also inhibit the repressive effect  of tumour suppressor p53. Some HDAC inhibitors can  prevent the formation of the new vessel [27].

Valproic acid is used in clinical trials for  different types of tumours such as colorectal, breast,  prostate, melanoma, NSCLC and pancreaticobiliary.  Benzamide derivative compounds are also used for the  clinical trial for leukaemia, pancreatic cancer,  lymphoma, Hodgkin’s lymphoma, SHH  medulloblastoma and other solid tumours. HDAC  inhibitors combined with PD-L1 antibodies can show  the antitumoral activity by modulating the gene  regulation [25]. The activity of  HDAC3 in HCT116 cells is inhibited by HDAC  inhibitor SFN which promotes the degradation of  HDAC3 and this facilitates the degradation and  acetylation of CtIP by weakening the interaction  between HDAC3 and CtIP. This modulates the HR  activity in cancer treatment [26]. Some  pan-HDAC inhibitors, as well as class-selective HDAC  inhibitors, are used for the treatment of neurodegenerative  disease [31]. A positive effect on  memory and synaptic plasticity has been shown due to the HDAC inhibitor and it also can be used as a mood  stabilizer. Negative regulation of long-term memory is  caused by HDAC3 [29].  
 

The chromatin decondensation due to the  deacetylation in H3 and H4 lysine residues can control  the transcription process and also influence DNA  repair, replication and cell differentiation [35]. 
The imbalance between acetylation and  deacetylation can lead to proliferation and  differentiation which causes several diseases and thus  epigenetic modification can be used in therapeutic drug developments. SIRT1 was reported to be used as an  important tool in the treatment of cardiovascular  disease. The damage caused by heart failure is protected  by SIRT1 and SIRT3 [6] [22]. HDAC inhibitors are widely  used for a clinical trial to increase the activity of the  drugs for the treatment of malignancies [13].  

It has been shown that the innate immune cell at the  transcription level can be controlled by acetylation.  Acetylation occurs in the enzymes that are involved in  the gluconeogenesis, glycolysis, TCA cycle, FAO, and  the urea cycle. The presence of SIRTs in mitochondria  is evident for the occurrence of the acetylation and  deacetylation within the mitochondria. Acetylation in  the mitochondrial proteins is responsible for several  malfunctions as well as linked to the nutrient levels  [9]. Histone modification can  also be controlled by metabolites and thus the histone  medication indirectly affects the metabolism. Some  metabolic products such as acetyl-CoA, fumarate,  SAM, succinate, 2-HG, NAM, NAD+, are used as the  substrate in histone modification, controlling the  metabolism process as well [2]. 
 

We would like to express our gratitude to Jadav  University and Heritage Institute of Technology for  providing us the opportunity and support to work on this  review.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: The study was approved by the Institutional Ethics Committee of Heritage Institute of Technology.
 

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