Epigenetics in human diseases
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This document discusses epigenetics and its role in human disease. It begins with an introduction to epigenetics, explaining that epigenetic processes can alter gene expression without changing DNA sequence. It then discusses some key epigenetic mechanisms like DNA methylation and histone modifications. It provides examples of how epigenetic changes are implicated in several diseases, such as neurological disorders, autoimmune diseases, diabetes, and cancer. The document concludes by noting that epigenetic therapies are being explored for diseases like cancer, and that combining epigenetic drugs with immunotherapy shows promise in treating various cancer types.
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Epigenetics in human diseases
- 1. EPIGENETICS IN HUMAN DISEASES Kamaleswari Balaji Medical Science Liaison
- 2. AGENDA • Introduction • Mechanism of epigenetics • Epigenetics in Human Diseases • Epigenetic therapy • Future Directions
- 4. INTRODUCTION TO EPIGENETICS • Epigenetics means “on top” or “in addition” to genetics. • Epigenetic processes include mitotically and/or meiotically heritable alterations to genetic information without changing the DNA sequence • It refers to external modifications to DNA that turn genes "on” or "off." These modifications do not change the DNA sequence, but instead, they affect how cells "read" genes. • Epigenome is made up of chemical compounds and proteins that can attach to DNA and direct such actions as turning genes on or off, controlling the production of proteins in particular cells.
- 9. HISTONE MODIFICATIONS • The first level of chromatin organization-nucleosome • histones H2A, H2B, H3, and H4 structured as an octameric core with DNA wrapped tightly around the octamer
- 11. HUMAN DISEASES AND EPIGENETICS
- 12. EPIGENETICS IN NEUROLOGICAL DISEASE • Schizophrenia and bipolar disorder-elevated DNMT1 levels were found in GABAergic neurons. • Alzheimer’s disease- significant DNA hypomethylation in the temporal neocortex has been observed • In autism-a cumulative effect of genetics (mutations in synaptic factors) and the environment has been suggested.
- 13. EPIGENETICS OF AUTOIMMUNE DISORDERS • Systemic lupus Erythematosus • Rheumatoid arthritis – DNA hypomethylation – DNMT1 suppression Shamsi B et al Journal of Taibah University Medical Sciences (2017) 12(3), 205-211
- 14. EPIGENETICS IN DIABETES Kuroda et al 2009 the promoter region of insulin producing beta cells is hypomethylated. demonstrated that expression of the insulin gene is negatively associated with DNA methylation at a CpG site located at 182 base pairs upstream of the insulin promoter. Further, H4 hyperacetylation and H3 dimethylation at lysine 4 were reported in patients with type 2 diabetes. Thus, the expression of epigenetic changes in pancreatic islets and beta cells significantly affects diabetes risk in individuals. Diabetic retinopathy is known to be associated with a number of epigenetic markers, including methylation of the Sod2 and MMP-9 genes, an increase in transcription of LSD1, a H3K4 and H3K9 demethylase, and various DNA Methyl-Transferases (DNMTs), and increased presence of miRNAs for transcription factors and VEGF Shamsi B et al Journal of Taibah University Medical Sciences (2017) 12(3), 205-211
- 15. Imprinting disorders • During imprinting, one allele from either parent is expressed while the other is silent (imprinted). • Imprinting errors are critical in numerous developmental and pediatric disorders. • Epigenetic abnormalities at chromosome 15 on the paternal allele lead to Pradere Willi syndrome • Epigenetic abnormalities at the same locus on the maternal allele of chromosome 15 cause Angelman syndrome
- 16. Epigenetics in Cancer • Jones and Baylin(2002) reported that microsatellites in colorectal and ovarian cancers are distorted by abnormal epigenetic modulations in the MLH1 promoter (a DNA repair gene). • Witcher and Emerson (2009) reported that the loss of chromatin domains and discrete histone structures are associated with dysregulation of transcriptional control of p16 in breast cancer cells • Efforts to sequence the genome of thousands of human cancers over the past decade have elucidated the presence of frequent alterations in numerous epigenetic regulators, recognizing unambiguously the key role of epigenetic deregulation in carcinogenesis
- 17. Roberti et al. Clinical Epigenetics (2019) 11:81
- 18. Lauren P et al DNA Cell Biol. 2012 Oct; 31(Suppl 1): S-49–S-61
- 20. Epigenetic modality of treatment are being experimented in the indications of Diabetic retinopathy, cardiac dysfunction, schizoprenia, autoimmune disorders and oncotherapy. Epigenetics in Therapy
- 21. Epigenetics in cancer Therapy Roberti et al. Clinical Epigenetics (2019) 11:81
- 22. DNA METHYLATION INHIBITORS (iDNMTS) • The first approved epigenetic drug was 5-azacitidine (Vidaza, Azacitidine), a iDNMT indicated in the treatment of patients with MDS and AML, followed 2 years later in 2006 by 5-aza-2′- deoxycytidine (decitabine (DAC), Dacogen). • These cytosine analogs inhibit DNMT in actively replicating cells, causing the loss of methylation marks during DNA replication, and consequently the reactivation of aberrantly silenced tumor suppressor genes. Roberti et al. Clinical Epigenetics (2019) 11:81
- 23. HISTONE DEACETYLASE INHIBITORS (iHDACS) • The USFDA has approved four iHDACs drugs. • Vorinostat (SAHA), approved for the treatment - cutaneous T cell lymphoma (CTCL), acts on class I, II, and IV HDACs and has been shown to induce apoptosis and cell cycle arrest, as well as to sensitize cancer cells to chemotherapy. • Belinostat selectively acts on class I and II HDACs and has been approved to treat peripheral T cell lymphomas (PTCL). • Romidepsin specifically targets class I HDACs and has been approved for both CTCL and PTCL patients. • Panobinostat, indicated for the treatment of drug-resistant multiple myeloma in combination with proteasome inhibitor brotezomid. Panobinostat is the only HDACi approved in Europe for clinical use Roberti et al. Clinical Epigenetics (2019) 11:81
- 24. EPIGENETICS IN DRUG RESISTANCE Alexandra B et al Epigenetic Diagnosis & Therapy Volume 1 , Issue 2 , 2015 The epigenome plays a key role in cancer heterogeneity and drug resistance.
- 25. EPIGENETICS WITH IMMUNOTHERAPY • Many cancer cells acquire immune evasive phenotypes that render them “invisible” to the immune system. • One of the rationales -cancer cells can employ epigenetic silencing to hide from the immune system by shutting off the expression of certain cell surface molecules that play a crucial role in the efficient recognition and elimination of “intruders” by the immune system. • It has been demonstrated that iDNMTs and iHDACs can reverse immune escape via several mechanisms. • Currently, ongoing clinical trials are evaluating combinations of epigenetic drugs and immunotherapy against many cancer types, including leukemias, metastatic melanoma, metastatic kidney cancer, peripheral neuroectodermal tumors, non-small cell lung cancer, and metastatic colorectal cancer
- 26. CAN WE SECURE A CURE ? Lauren P et al DNA Cell Biol. 2012 Oct; 31(Suppl 1): S-49–S-61
- 27. SUMMARY • Genome contain the information from the DNA sequence , while the epigenome affects how these information is read. • Epigenetics is relatively new compared to that of genetics and is being experimented for futuristic methods of Diagnosis, Therapy and prognosis of various forms of diaseases.
- 28. Thank You
Editor's Notes
- HUMAN BODY –ORGAN SYSTEMS –ORGANS ORGANS –CELLS CELLS –DNA DNA-NUCLEOTIDE BASES IN DOUBLE HELIX HISTONE BODEIS GENES –Proteins
- epigenetics is the study of heritable phenotype changes that do not involve alterations in the DNA sequence. Epigenetics not only considers the genomic constitution, but also integrates the social and natural environment, influence of everyday routine, dietary habits, and stresses to biological systems.These stimuli-initiated modulations of the epigenome contribute to embryo development, cell differentiation, and responses to exogenous signals. Thus, in contrast to the consistency of the genome, plasticity in the epigenome is characterized by dynamic and flexible responses to intracellular and extracellular stimuli including those from the environment. When epigenomic compounds attach to DNA and modify its function, they are said to have "marked" the genome. These marks do not change the sequence of the DNA. Rather, they change the way cells use the DNA's instructions. The marks are sometimes passed on from cell to cell as cells divide. They also can be passed down from one generation to the next.
- DNA methylation, histone modification, and micro RNA (miRNA) expression work together to control the complex environment of epigenetics in cancer. Promoter hypomethylation is linked to the expression of genes, including miRNA, DNA methyltransferases (DNMTs), and histone modifiers (1). DNMTs can, in turn, hypermethylate promoters and turn off these same genes (2). Histone-modifying enzymes can affect gene expression by adding or removing certain marks (3). miRNAs are processed and targeted to mRNA, leading to a decrease in the protein expression of certain enzymes (4).
- DNA methylation takes place at the 5 dash position in the pyrimidine ring to covalently link a methyl group to the cytosine. At cytosine located prior to guanine in the genome forms CpG sites, which are abundantly present in the promoters of protein-coding genes. Methylation and demethylation of these CpG sites regulate transcription and gene expression. DNA methylation is maintained by a variety of DNA methyltransferases (DNMTs) that are present in biological systems. Approximately 40% of mammalian genes have stretches of CpGs within their promoter regions; methylation of these sites leads to heritable transcriptional silencing. De novo methylation errors at CpGs in the promoter region are indicators of human diseases and have been detected during early tumourigenesis
- Acetylation and methylation of lysine residues at the amino-terminal tail domains of histone - epigenetic modifiers.
- MicroRNAs (miRNA) and small interfering RNAs play important roles in RNA-associated silencing, during which they downregulate gene expression at the posttranscriptional modification stage. Post-transcriptional binding of non-coding RNA to 30-untranslated regions of target mRNAs acts as a putative RNA silencing mechanism. These RNAs act as switches and modulators to fine-tune gene expression during normal development and in diseases. Additionally, miRNAs play an important role in tumour suppression, apoptosis, cellular proliferation, and cell movement
- SLE is an autoimmune disorder characterized by multisystem inflammation with the generation of autoantibodies. Although the specific cause of SLE is unknown, multiple factors are associated with the development of the disease, including genetic, epigenetic, ethnic, immunoregulatory, hormonal, and environmental factors. [9, 10, 11, 12] Many immune disturbances, both innate and acquired, occur in SLE (see the image below).Animal models with mutations affecting the epigenome showed reduced DNA methylation and suppressed DNMT1 expression in T-cells, which directly correlates with aging and SLE progression In patients with arthritis, global DNA hypomethylation is found in the blood, synovial mononuclear cells, and synovial tissue.
- During tumorigenesis, the epigenome goes through multiple alterations, including genome-wide loss of DNA methylation and regional hypermethylation, espe cially in CpG promoter islands of tumor suppressor genes [31–34], global changes in histone modification marks [34–36], and deregulation in the networks in which ncRNAs engage
- Examples of epigenetic alterations in cancer cells. Hypermethylation of promoters of tumor suppressor genes, global loss of H4K20me3 and H4K16ac, and up- or downregulation of miRNAs that target oncogenes and tumor suppressor genes, respectively. During tumorigenesis, the epigenome goes through multiple alterations, including genome-wide loss of DNA methylation and regional hypermethylation, espe cially in CpG promoter islands of tumor suppressor genes [31–34], global changes in histone modification marks [34–36], and deregulation in the networks in which ncRNAs engage
- 5% of patients with cancer will be diagnosed with cancer of unknown origin." "These patients not only have a poor prognosis," says Carmen Balañá from the Catalan Institute of Oncology Germans Trias i Pujol, "but also when we don't know the origin of the tumor that gave rise to metastasis, they are given a treatment empirically. Indeed, in many cases, negatively affect both the progression of the disease and quality of life for patients.“ finding methylation profiling to help us identify what treatments could be sensitive within the tumor, EPICUP has great specificity and sensitivity owing to it being based on DNA methylation profiles which classify CUPs with respect to samples of known origin, including 38 tumor types and 85 metastases
- The cancer epigenome is characterized by simultaneous global losses in DNA methylation (indicated by pale blue circles) with hundreds of genes that have abnormal gains of DNA methylation (indicated by red circles) and repressive histone modifications (indicated by red flags) in promoter region CpG islands. The hypomethylated regions have an abnormally open nucleosome configuration and abnormally acetylated histone lysines (indicated by green flags). Conversely, abnormal DNA hypermethylation in promoter CpG islands is associated with nucleosomes positioned over the transcription start sites of the associated silenced genes (indicated by an arrow with a red X). Recent whole-exon sequencing of human cancers has shown a high proportion of mutations in genes in leukaemias, lymphomas, and ovarian, renal and pancreatic cancers, and rhabdomyosarcoma109–111,154–156 (indicated in yellow boxes), which are depicted as helping to mediate either abnormal DNA methylation, histone modifications and/or nucleosome remodelling100,107,108,118,155,157–165. ARID1A, AT-rich interactive domain-containing protein 1A; DNMT3A, DNA methyltransferase 3A; EZH2, ehancer of zeste 2; IDH1, isocitrate dehydrogenase 1; MLL, mixed lineage leukaemia; PBRM1, protein polybromo 1; SNF5, SWI/SNF-related, matrix associated, actin-dependent regulator of chromatin, subfamily B, member 1; VHL, Von Hippel–Lindau
- Both the plasticity and the reversible nature of epigenetic modifications make them ideal potential druggable targets for anticancer strategies, the idea being that they enable the resetting of the cancer epigenome. Epidrugs can be classified on the basis of their respective target enzyme. Although at present only two classes of epigenetic drugs have been approved by the US Food and Drug Administration (FDA)—DNA methylation inhibitors (iDNMTs) and histone deacetylase inhibitors (iHDACs)—several new targets are in late-stage clinical trials and show therapeutic promise
- Resistance of malignant cells to chemotherapy and molecularly targeted therapy is a major roadblock in our effort to cure cancer. A variety of underlying mechanisms have been described, some of which are shared between resistance to chemotherapy and resistance to molecularly targeted therapy. Although the influence of genetic mutations in the development of drug resistance is beyond question, many examples now support the contribution of epigenetic changes to drug resistance. Several clinical trials are under way to explore the effectiveness of epigenetics-targeting drugs to reverse or overcome resistance to cancer therapies. In addition to these strategies, we suggest a complementary approach that could utilize epigenetics-targeting drugs to prevent drug resistance.
- Studying the epigenetic links shared by common cancers provides exciting potential for a powerful anticancer drug targeting many forms of the disease. Conversely, profiling the epigenetic differences between certain cancers will allow us to design more specific drugs. Elucidating and detailing these differences and the differences in the epigenetics of diseased versus normal tissue will allow the continued development of drugs that are unique to those diseases.