Gene therapy is a focus of interest in both human and veterinary medicine, especially in recent years due to the potential applications of CRISPR/Cas9 technology. Another relatively new approach is that of epigenetic therapy, which involves an intervention based on epigenetic marks, including DNA methylation, histone post-translational modifications, and post-transcription modifications of distinct RNAs. The epigenome results from enzymatic reactions, which regulate gene expression without altering DNA sequences. In contrast to conventional CRISP/Cas9 techniques, the recently established methodology of epigenetic editing mediated by the CRISPR/dCas9 system is designed to target specific genes without causing DNA breaks. Both natural epigenetic processes and epigenetic editing regulate gene expression and thereby contribute to maintaining the balance between physiological functions and pathophysiological states. From this perspective, knowledge of specific epigenetic marks has immense potential in both human and veterinary medicine. For instance, the use of epigenetic drugs (chemical compounds with therapeutic potential affecting the epigenome) seems to be promising for the treatment of cancer, metabolic, and infectious diseases. Also, there is evidence that an epigenetic diet (nutrition-like factors affecting epigenome) should be considered as part of a healthy lifestyle and could contribute to the prevention of pathophysiological processes. In summary, epigenetic-based approaches in human and veterinary medicine have increasing significance in targeting aberrant gene expression associated with various diseases. In this case, CRISPR/dCas9, epigenetic targeting, and some epigenetic nutrition factors could contribute to reversing an abnormal epigenetic landscape to a healthy physiological state.

Department of Cell Biology and Epigenetics Institute of Biophysics Academy of Sciences of the Czech Republic Brno 612 00 the Czech Republic

See more in PubMed

Barbieri  I, Kouzarides  T. Role of RNA modifications in cancer. Nat Rev Cancer  2020;20:303–22. PubMed

Cui  L, Ma  R, Cai  J  et al.  RNA modifications: importance in immune cell biology and related diseases. Signal Transduct Target Ther  2022;7:334. PubMed PMC

Goldberg  AD, Allis  CD, Bernstein  E. Epigenetics: a landscape takes shape. Cell  2007;128:635–8. PubMed

Allen  M. Compelled by the diagram: thinking through C. H. Waddington’s Epigenetic Landscape. Contemporaneity  2015;4:119.

Hardy  TM, Tollefsbol  TO. Epigenetic diet: impact on the epigenome and cancer. Epigenomics  2011;3:503–18. PubMed PMC

Jones  PA, Ohtani  H, Chakravarthy  A  et al.  Epigenetic therapy in immune-oncology. Nat Rev Cancer  2019;19:151–16.1. PubMed

Lan  X, Evan  C, Cretney  J  et al.  Maternal diet during pregnancy induces gene expression and DNA methylation changes in fetal tissues in sheep. Front Genet  2013;4:49. PubMed PMC

McArthur  E, Capra  JA. Topologically associating domain boundaries that are stable across diverse cell types are evolutionarily constrained and enriched for heritability. Am J Hum Genet  2021;108:269–83. PubMed PMC

Rajderkar  S, Barozzi  I, Zhu  Y  et al.  Topologically associating domain boundaries are required for normal genome function. Commun Biol  2023;6:435. PubMed PMC

Woodcock  CL, Ghosh  RP. Chromatin higher-order structure and dynamics. Cold Spring Harb Perspect Biol  2010;2:a000596. PubMed PMC

Moore  L, Le  T, Fan  G. DNA methylation and its basic function. Neuropsychopharmacol  2013;38:23–38. PubMed PMC

Adam  S, Anteneh  H, Hornisch  M  et al.  DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation. Nat Commun  2020;11:3723. PubMed PMC

Wu  X, Zhang  Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet  2017;18:517–34. PubMed

Rasmussen  KD, Helin  K. Role of TET enzymes in DNA methylation, development and cancer. Genes Dev  2016;30:733–50. PubMed PMC

Bayraktar  G, Kreutz  MR. The role of activity-dependent DNA demethylation in the adult brain and in neurological disorders. Front Mol Neurosci  2018;11:169. PubMed PMC

Takeshima  H, Yoda  Y, Wakabayashi  M  et al.  Low-dose DNA demethylating therapy induces reprogramming of diverse cancer-related pathways at the single-cell level. Clin Epigenet  2020;12:142. PubMed PMC

Turner  B. Reading signals on the nucleosome with a new nomenclature for modified histones. Nat Struct Mol Biol  2005;12:110–2. PubMed

Bannister  A, Kouzarides  T. Regulation of chromatin by histone modifications. Cell Res  2011;21:381–95. PubMed PMC

Williamson  EA, Wray  JW, Bansal  P  et al.  Overview for the histone codes for DNA repair. Prog Mol Biol Transl Sci  2012;110:207–27. PubMed PMC

Shi  Y, Whetstine  JR. Dynamic regulation of histone lysine methylation by demethylases. Mol Cell  2007;25:1–14. PubMed

Wissmann  M, Yin  N, Müller  JM. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat Cell Biol  2007;9:347–53. PubMed

Vicioso-Mantis  M, Aguirre  S, Martínez-Balbás  MA. JmjC family of histone demethylases form nuclear condensates. Int J Mol Sci  2022;23:7664. PubMed PMC

Couture  JF, Collazo  E, Ortiz-Tello  PA  et al.  Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase. Nat Struct Mol Biol  2007;14:689–95. PubMed

Das  A, Chai  JC, Jung  KH  et al.  JMJD2A attenuation affects cell cycle and tumourigenic inflammatory gene regulation in lipopolysaccharide stimulated neuroectodermal stem cells. Exp Cell Res  2014;328:361–78. PubMed

Mallette  F, Mattiroli  F, Cui  G  et al.  RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites. EMBO J  2012;31:1865–78. PubMed PMC

Berry  WL, Shin  S, Lightfoot  SA  et al.  Oncogenic features of the JMJD2A histone demethylase in breast cancer. Int J Oncol  2012;41:1701–6. PubMed

Seto  E, Yoshida  M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harbor Perspect Biol  2014;6:a018713. PubMed PMC

Narita  T, Weinert  BT, Choudhary  C. Functions and mechanisms of non-histone protein acetylation. Nat Rev Mol Cell Biol  2019;20:156–74. PubMed

Park  SY, Kim  JS. A short guide to histone deacetylases including recent progress on class II enzymes. Exp Mol Med  2020;52:204–12. PubMed PMC

Peng  L, Seto  E. Deacetylation of nonhistone proteins by HDACs and the implications in cancer. Handb Exp Pharmacol  2011;206:39–56. PubMed

Večeřa  J, Bártová  E, Krejčí  J  et al.  HDAC1 and HDAC3 underlie dynamic H3K9 acetylation during embryonic neurogenesis and in schizophrenia-like animals. J Cell Physiol  2018;233:530–48. PubMed PMC

Miranda Furtado  CL, Santos Luciano MC  D, Silva Santos  RD  et al.  Epidrugs: targeting epigenetic marks in cancer treatment. Epigenetics  2019;14:1164–76. PubMed PMC

Gladkova  MG, Leidmaa  E, Anderzhanova  EA. Epidrugs in the therapy of central nervous system disorders: a way to drive on?  Cells  2023;12:1464. PubMed PMC

Nie  J, Liu  L, Li  X  et al.  Decitabine, a new star in epigenetic therapy: the clinical application and biological mechanism in solid tumors. Cancer Lett  2014;354:12–20. PubMed

Wawruszak  A, Borkiewicz  L, Okon  E  et al.  Vorinostat (SAHA) and breast cancer: an overview. Cancers (Basel)  2021;13:4700. PubMed PMC

Ciechomska  I, Przanowski  P, Jackl  J  et al.  BIX01294, an inhibitor of histone methyltransferase, induces autophagy-dependent differentiation of glioma stem-like cells. Sci Rep  2016;6:38723. PubMed PMC

Dalpatraj  N, Naik  A, Thakur  N. GSK-J4: an H3K27 histone demethylase inhibitor, as a potential anti-cancer agent. Int J Cancer  2023;153:1130–8. PubMed

Reuter  S, Gupta  SC, Park  B  et al.  Epigenetic changes induced by curcumin and other natural compounds. Genes Nutr  2011;6:93–108. PubMed PMC

Peng  Y, Ao  M, Dong  B  et al.  Anti-inflammatory effects of curcumin in the inflammatory diseases: status, limitations and countermeasures. Drug Des Devel Ther  2021;15:4503–25. PubMed PMC

Song  T, Lv  S, Li  N  et al.  Versatile functions of RNA m6A machinery on chromatin. J Mol Cell Biol  2022;14:mjac011. PubMed PMC

Yelland  JN, Bravo  JPK, Black  JJ  et al.  A single 2′-O-methylation of ribosomal RNA gates assembly of a functional ribosome. Nat Struct Mol Biol  2023;30:91–8. PubMed PMC

Zhang  C, Jia  G. Reversible RNA modification N1-methyladenosine (m1A) in mRNA and tRNA. Genomics Proteomics Bioinf  2018;16:155–61. PubMed PMC

Dominissini  D, Rechavi  G. 5-methylcytosine mediates nuclear export of mRNA. Cell Res  2017;27:717–9. PubMed PMC

Slotkin  W, Nishikura  K. Adenosine-to-inosine RNA editing and human disease. Genome Med  2013;5:105. PubMed PMC

Wu  G, Huang  C, Yu  YT. Pseudouridine in mRNA: incorporation, detection, and recoding. Methods Enzymol  2015;560:187–217. PubMed PMC

Nance  KD, Gamage  ST, Alam  MM  et al.  Cytidine acetylation yields a hypoinflammatory synthetic messenger RNA. Cell Chem Biol  2022;29:312–20.e7. PubMed PMC

Arango  D, Sturgill  D, Alhusaini  N  et al.  Acetylation of cytidine in mRNA promotes translation efficiency. Cell  2018;175:1872–86.e24. PubMed PMC

Dalhat  MH, Altayb  HN, Khan  MI  et al.  Structural insights of human N-acetyltransferase 10 and identification of its potential novel inhibitors. Sci Rep  2021;11:6051. PubMed PMC

Kirschner  J, Cathomen  T. Gene therapy for monogenic inherited disorders. Dtsch Arztebl Int  2020;117:878–85. PubMed PMC

Elangkovan  N, Dickson  G, Jaiswal  J. Gene therapy for duchenne muscular dystrophy. J Neuromuscul Dis  2021;8:S303–16. PubMed PMC

Jogalekar  MP, Rajendran  RL, Khan  F  et al.  CAR T-cell-based gene therapy for cancers: new perspectives, challenges, and clinical developments. Front Immunol  2022;13:925985. PubMed PMC

Sudhakar  V, Richardson  RM. Gene therapy for neurodegenerative diseases. Neurotherapeutics  2019;16:166–75. PubMed PMC

Choi  EH, Suh  S, Sears  AE  et al.  Genome editing in the treatment of ocular diseases. Exp Mol Med  2023;55:1678–90. PubMed PMC

Pavlin  D, Cemazar  M, Sersa  G  et al.  IL-12 based gene therapy in veterinary medicine. J Transl Med  2012;10:234. PubMed PMC

Argyle  DJ. Gene therapy in veterinary medicine. Vet Rec  1999;144:369–76. PubMed

Zhang  Y, Peng  Q, Zhang  R  et al.  Advances in CRISPR/Cas-based strategies on zoonosis. Transbound Emerg Dis  2023.

Doudna  JA, Charpentier  E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science  2014;346:1258096. PubMed

Ran  F, Hsu  P, Wright  J  et al.  Genome engineering using the CRISPR-Cas9 system. Nat Protoc  2013;8:2281–308. PubMed PMC

Wang  JY, Doudna  JA. CRISPR technology: a decade of genome editing is only the beginning. Science  2023;379:eadd8643. PubMed

Xu  W, Jiang  X, and Huang  L. RNA interference technology. Comprehensive Biotechnol  2019;560–75. doi: 10.1016/B978-0-444-64046-8.00282-2 DOI

Song  B, Yang  S, Hwang  GH  et al.  Analysis of NHEJ-based DNA repair after CRISPR-mediated DNA cleavage. Int J Mol Sci  2021;22:6397. PubMed PMC

Chatterjee  N, Walker  GC. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen  2017;58:235–63. PubMed PMC

Huang  R, Zhou  PK. DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy. Sig Transduct Target Ther  2021;6:254. PubMed PMC

Lemaître  C, Grabarz  A, Tsouroula  K  et al.  Nuclear position dictates DNA repair pathway choice. Genes Dev  2014;28:2450–63. PubMed PMC

Kakarougkas  A, Jeggo  PA. DNA DSB repair pathway choice: an orchestrated handover mechanism. Br J Radiol  2014;87:20130685. PubMed PMC

Molina  A, Bonnet  F, Lobjois  V  et al.  G1 phase lengthening during neural tissue development involves CDC25B induced G1 heterogeneity. bioRxiv  2020.

Li  VC, Ballabeni  A, Kirschner  MW. Gap 1 phase length and mouse embryonic stem cell self-renewal. Proc Natl Acad Sci USA  2012;109,12550–5. PubMed PMC

Ahuja  A, Jodkowska  K, Teloni  F  et al.  A short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells. Nat Commun  2016;7:10660. PubMed PMC

Yang  D, Scavuzzo  M, Chmielowiec  J  et al.  Enrichment of G2/M cell cycle phase in human pluripotent stem cells enhances HDR-mediated gene repair with customizable endonucleases. Sci Rep  2016;6:21264. PubMed PMC

Hendel  A, Bak  RO, Clark  JT  et al.  Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells. Nat Biotechnol  2015;33:985–9. PubMed PMC

Anzalone  AV, Randolph  PB, Davis  JR  et al.  Search-and-replace genome editing without double-strand breaks or donor DNA. Nature  2019;576:149–57. PubMed PMC

Saunderson  EA, Encabo  HH, Devis  J  et al.  CRISPR/dCas9 DNA methylation editing is heritable during human hematopoiesis and shapes immune progeny. Proc Natl Acad Sci USA  2023;120:e2300224120. PubMed PMC

Lu  A, Wang  J, Sun  W  et al.  Reprogrammable CRISPR/dCas9-based recruitment of DNMT1 for site-specific DNA demethylation and gene regulation. Cell Discov  2019;5:22. PubMed PMC

Ashfaq  MA, Kumar  VD, Reddy  PSS  et al.  Post-transcriptional gene silencing: basic concepts and applications. J Biosci  2020;45:128. PubMed

Singh  K, Erdman  RA, Swanson  KM  et al.  Epigenetic regulation of milk production in dairy cows. J Mammary Gland Biol Neoplasia  2010;1:101–12. PubMed

Xue  Q, Huang  Y, Cheng  C  et al.  Progress in epigenetic regulation of milk synthesis, with particular emphasis on mRNA regulation and DNA methylation. Cell Cycle  2023;22:1675–93. PubMed PMC

Lesta  A, Marín-García  PJ, Llobat  L. How does nutrition affect the epigenetic changes in dairy cows?  Animals (Basel)  2023;13:1883. PubMed PMC

Melnik  BC. Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases. J Transl Med  2015;13:385. PubMed PMC

Melnik  BC, Gerd  S. Milk exosomes and microRNAs: potential epigenetic regulators. In: Patel  V (ed), Handbook of Nutrition, Diet, and Epigenetics. Springer, 2017.

Bodo  C, Melnik  GS. DNA methyltransferase 1-targeting miRNA-148a of dairy milk: a potential bioactive modifier of the human epigenome. Funct Foods Health Dis  2017;7:671–87.

Cai  X, Liu  Q, Zhang  X  et al.  Identification and analysis of the expression of microRNA from lactating and nonlactating mammary glands of the Chinese swamp buffalo. J Dairy Sci  2017;100:1971–86. PubMed

Carrillo-Lozano  E, Sebastián-Valles  F, Knott-Torcal  C. Circulating microRNAs in breast milk and their potential impact on the infant. Nutrients  2020;12:3066. PubMed PMC

Lee  EY, Muller  WJ. Oncogenes and tumor suppressor genes. Cold Spring Harb Perspect Biol  2010;2:a003236. PubMed PMC

Lyu  J, Li  JJ, Su  J  et al.  DORGE: discovery of oncogenes and tumor suppressor genes using genetic and epigenetic features. Sci Adv  2020;6: eaba6784. PubMed PMC

Kwon  MJ, Shin  YK. Epigenetic regulation of cancer-associated genes in ovarian cancer. Int J Mol Sci  2011;12:983–1008. PubMed PMC

Li  Y, Seto  E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb Perspect Med  2016;6:a026831. PubMed PMC

Zhang  Q, Wang  S, Chen  J  et al.  Histone deacetylases (HDACs) guided novel therapies for T-cell lymphomas. Int J Med Sci  2019;16:424–42. PubMed PMC

Vaccaro  JA, Naser  SA. The role of methyl donors of the methionine cycle in gastrointestinal infection and inflammation. Healthcare (Basel)  2021;10:61. PubMed PMC

Hassan  FU, Rehman  MS, Khan  MS  et al.  Curcumin as an alternative epigenetic modulator: mechanism of action and potential effects. Front Genet  2019;10:514. PubMed PMC

Kok  DEG, Dhonukshe-Rutten  RAM, Lute  C  et al.  The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects. Clin Epigenet  2015;7:121. PubMed PMC

Fernandes  GFS, Silva  GDB, Pavan  AR  et al.  Epigenetic regulatory mechanisms induced by resveratrol. Nutrients  2017;9:1201. PubMed PMC

Boyanapalli  SSS, Kong  AN. “Curcumin, the king of spices”: epigenetic regulatory mechanisms in the prevention of cancer, neurological, and inflammatory diseases. Curr Pharmacol Rep  2015;1:129–39. PubMed PMC

Mansouri  K, Rasoulpoor  S, Daneshkhah  A  et al.  Clinical effects of curcumin in enhancing cancer therapy: a systematic review. BMC Cancer  2020;20:791. PubMed PMC

Shanmugam  MK, Rane  G, Kanchi  MM  et al.  The multifaceted role of curcumin in cancer prevention and treatment. Molecules  2015;20:2728–69. PubMed PMC

Mishra  S, Palanivelu  K. The effect of curcumin (turmeric) on Alzheimer’s disease: an overview. Ann Indian Acad Neurol  2008;11:13–9. PubMed PMC

Boonrueng  P, Wasana  PWD, Hasriadi,Vajragupta  O  et al.  Combination of curcumin and piperine synergistically improves pain-like behaviors in mouse models of pain with no potential CNS side effects. Chin Med  2022;17:119. PubMed PMC

Skinner  MK. Environmental epigenetics 2023 update. Environ Epigenet  2023;9:dvad004. PubMed PMC

Mirbahai  L, Chipman  JK. Epigenetic memory of environmental organisms: a reflection of lifetime stressor exposures. Mutat Res/Genet Toxicol Environ Mutagen  2014;764–765:10–7. PubMed

Probst  AV, Mittelsten Scheid  O. Stress-induced structural changes in plant chromatin. Curr Opin Plant Biol  2015;27:8–16. PubMed

Kovařík  A, Koukalová  B, Bezděk  M  et al.  Hypermethylation of tobacco heterochromatic loci in response to osmotic stress. Theor Appl Genet  1997;95:301–6.

Widiez  T, Symeonidi  A, Luo  C  et al.  The chromatin landscape of the moss Physcomitrella patens and its dynamics during development and drought stress. Plant J  2014;79:67–81. PubMed

Pecinka  A, Dinh  HQ, Baubec  T  et al.  Epigenetic regulation of repetitive elements is attenuated by prolonged heat stress in Arabidopsis. The Plant Cell  2010;22:3118–29. PubMed PMC

Schenke  D, Cai  D, Scheel  D. Crosstalk between abiotic UV-B and biotic stress depends on H3K9 acetylation. Plant Cell Environ  2014;37:1716–21. PubMed