Epigenetics in human diseases

your DNA is not your destiny

1. EPIGENETICS IN HUMAN DISEASES Kamaleswari Balaji Medical Science Liaison

2. AGENDA Introduction Mechanism of epigenetics Epigenetics in Human Diseases Epigenetic therapy Future Directions

3. 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.

4. EPIGENETICS IN PHYSIOLOGY

5. EPIGENETIC MECHANISM

6. DNA METHYLATION

7. 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

8. RNA-associated silencing

9. Human diseases and Epigenetics

10. 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.

11. 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

12. 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

13. 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

14. 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

15. Roberti et al. Clinical Epigenetics (2019) 11:81

16. Lauren P et al DNA Cell Biol. 2012 Oct; 31( Suppl 1): S-49–S-61

17. EPIGENETICS IN DIAGNOSIS http://www.idibell.cat/en/whats-on/noticies/ferrer-and-idibell-develop-epicup-first-epigenetic-test-patients-cancer

18. Epigenetic modality of treatment are being experimented in the indications of Diabetic retinopathy, cardiac dysfunction, schizoprenia , autoimmune disorders and oncotherapy . Epigenetics in Therapy

19. Epigenetics in cancer Therapy Roberti et al. Clinical Epigenetics (2019) 11:81

20. 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 ). T hese 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

21. 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

22. 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.

23. 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

24. CAN WE SECURE A CURE ? Lauren P et al DNA Cell Biol. 2012 Oct; 31( Suppl 1): S-49–S-61

25. 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 .

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