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MyHVP Newsletter Volume 03 | Issue 01 | June 2016

Sixth Biennial Meeting of the Human Variome Project Consortium

30th May - 3rd June 2016 UNESCO Headquarters, Paris, France

Participants of the Sixth Biennial Meeting of the Human Variome Project (HVP) Consortium in Paris.

The

6th Biennial Meeting of the Human Variome Project (HVP) Consortium was held in the UNESCO Headquarters, Paris, France. The meeting marked ten years of the HVP’s collaboration and commitment to global collection and open sharing of genomic knowledge among the 1200 HVP members from 81 countries. The 6th biennial meeting was significant with the absence of the founding Patron Prof. Richard Cotton, who sadly passed away last year.

The event started with a two-day Satellite Meeting on The Global Globin 2020 (GG2020) Challenge. The welcome speech was given by Professor Zilfalil bin Alwi who gave an overview of the GG2020 challenge. This was followed by presentations by members on the current status of GG2020 in different parts of the globe and a session on databases and data sharing. The second day of the GG2020 Challenge started with the presentation on Glucose-6-Phosphate (G6PD) deficiency and its current situation in Malaysia by Professor Dr Narazah. This was followed by presentations by other members on Funding, Sharing Resources and Ethics, Legal and Social Issues (ELSI).

Among the objectives of the meeting was to set a new road map for the next four years. It is critical for the HVP to chart its future position and activities in a rapidly growing international field of genetic and genomic players. The HVP meeting commenced on the third day (Wednesday, 1st June) and concluded on 3rd

June. The welcome address was given by Chris Arnold, the Chair of HVP International Board. The session was chaired by Sir John Burn. The session focussed on lectures by speakers from various areas of expertise which included ELSI, Genes and Databases and Variation Interpretation among others. A total of 10 posters were presented by members and participants in the meeting. The meeting provided critical opportunity for discussion, consideration and formulation of plans and activities for the HVP to trailblaze the ever expanding frontiers of genetics and genomics. | The photo diary is on page 8 Reported by Professor Dr Narazah Mohd Yusoff, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Bertam, Penang & MyHVP member

Contact us: | Secretariat Office: Human Variome Project Malaysian Node & South-east Asian Node School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kota Bharu, Kelantan, Malaysia | Phone :(60) 097676543 / 6531 | Fax: (60) 097676543 | Email : myhvp@usm.my | Website: hvpmalaysia.kk.usm.my


MyHVP Newsletter

Head’s Address

Board of Editors 2016 Volume 03 | Issue 01 | June 2016

The

Editor in Chief Professor Dr. Zilfalil Alwi

Sixth Biennial Meeting of the Human Variome Project was held at UNESCO Headquarters, Paris from 1st June 2016 until 3rd June 2016. It was a successful meeting as it had brought together many of the prominent professionals in human genetics from around the world. The meeting provided updates on the achievements of Human Variome Project (HVP) over the past two years and a platform for discussion on the plans for the next two years.

Managing Editor Prof. Dr. Wan Zaidah Abdullah Editorial Board Members Prof. Ida Madieha binti Azmi Assoc. Prof. Dr. Endom Ismail Assoc. Prof. Dr Rosnah Bahar Dr. Nik Norliza Bt Nik Hassan Dr. Muhammad Farid Johan Dr. Azlina bt Ahmad Annuar Mr. Abdul Halim Fikri Bin Hashim English Editor Amyzar Alwi

Contents

02 Head’s Address 05 HVP Global 03 Report 07 Postgradu 04 When a Geneti- ate cist Writes 08 Photo Diary © 2016. All rights reserved. The information in this newsletter is provided by the Malaysian Node of the Human Variome Project (MyHVP) members including South-east Asian Node (HVPSEA Node) for educational / information purpose only. It is not a substitute for professional medical care and medical advice. The contents express the opinions of the authors who alone are responsible for their view expressed. MyHVP does not accept any legal responsibility for their contents.

Writers, Invited!

For the coming issue, we are going to invite the public from various fields and specialties in order to share with us, their experience in dealing with the issues of medicine or biomedicine. Writers may contribute their writing with these following criteria: 1. Length (Max. 1page A4 size, and it may be edited for our use) 2. The committee has the right to share your writing for further issues. 3. To suit the needs of the publication, and your writing won’t be returned 4. Emailed the article to myhvp@usm.my

The highlight of the workshop was a discussion entitled “The way forward 2016 and beyond” by a panel comprising Prof Raj Ramesar, Prof Zilfalil Bin Alwi, Prof Jacques Elion and Dr Carsten Lederer. As a global initiative, GG2020 will apply recent developments in human genomics involving the systematic collection and sharing of genetic variation data to fighting Haemoglobinopathies with initial focus on Thalassaemia, Sickle Cell disease and G6PD. The GG2020 Challenge hopes to build an evidence base for an efficient During the HVP6 meeting, Chris Arnold, management of local treatment, care chairman of the Human Variome Project and eventually cure for these diseases by International Board, unveiled the Pro- ensuring a sufficient local capacity in geject Roadmap 2016 – 2020. The Project netics and genomics to deliver services in Roadmap 2016 – 2020 is the third medi- these countries. um-term strategic plan produced by HVP. The road map articulates the planning of I would like to thank the hardworking edthe strategic scientific direction for the itorial board members for publishing this project and the targeted future of the pro- sixth publication of MyHVP Newsletter. ject in 2020. The latest roadmap aims to Last but not least, I invite all academics increase the accessibility of public sharing and researchers from institutions throughof information about clinically validated out Malaysia to join us in this global netand classified genomic variants with var- work of collaboration. ious individuals, organisations at national and international levels. Thank you. As the co-chair of Global Globin Challenge 2020 (GG2020 Challenge), it is my pleasure to announce that prior to the HVP6th meeting, a two-day workshop on GG2020 was held to discuss about the project. The workshop was attended by 32 participants from 16 countries with 11 out of 16 countries representative of countries where HVP node have been established. The workshop was funded by the March of Dimes through the American College of Medical Genetics. The number of participants in GG2020 has significantly increased from 40 to 62 countries. There are more than 20 partners and experts associated with GG2020.

Prof. Dr. Zilfalil Alwi Head, Malaysian Node of the Human Variome Project Universiti Sains Malaysia (Health Campus)

MyHVP Newsletter | June 2016 | page 2


Report Knowledge Program with National Council of Professor (MPN) with Terengganu Communities 26 - 27 May 2016, Kg. Bukit Wan, Kuala Nerus, Terengganu Prepared by Abdul Halim Fikri Hashim

School of Medical Sciences, Universiti Sains Malaysia, Health Campus and a Member of MyHVP

On

26 & 27 May 2016, the National Council of Professor Malaysia (MPN) organised a public community engagement activity at Bukit Wan, Kuala Nerus, Terengganu. The target participants were the community of Kg. Bukit Wan. The Malaysian Node of the Human Variome Project (MyHVP) was invited to educate the public on the importance of pre-marriage screening for thalassemia among teenagers. The talk on the thalassemia disease on 27 May 2016 was delivered by Dr Surini Yusoff and Dr. Shafini Bt. Mohamed Yusoff from the School of Medical Sciences, Universiti Sains Malaysia (USM) Kubang Kerian and members of MyHVP. The talk focussed on Hb/E is as the most common among the Malay ethnic group in Malaysia with its prevalence at 5%. Thus, without public education on the Dr. Shafini was delivering a talk entitled the importance of thalassemia screening importance of thalassemia screening, patients, families and the government will consequently bear the burden of the management of the disease. The cost for the treatments is expensive and requires commitment. Thus, early screening is a must, because knowing one’s thalassemia status as early as possible could prevent a person from suffering a prolonged difficulty. As part of awareness-raising activity, the MyHVP also set up open booths as part of health exhibition especially for thalassemia disease. The program ended at 4.30pm with the official closing ceremony officiated by the representative of Menteri Besar of Terengganu. | The Photo Diary is on page 8

Seminar on Human Genetics in conjunction with Annual General Meeting of MSHG (Malaysian Society of Human Genetics) 2016 25 February 2016, Auditorium Rimba Ilmu Univeristy of Malaya Kuala Lumpur Prepared by Abdul Halim Fikri Hashim

School of Medical Sciences, Universiti Sains Malaysia, Health Campus and a Member of MyHVP

On

25th February 2016, the MyHVP and the Malaysian Society of Human Genetics (MSHG) co-organised a seminar on human genetics at Auditorium Rimba Ilmu, University of Malaya, Kuala Lumpur in conjunction with Annual General Meeting (AGM). The seminar was attended by 40 participants who were mostly members of MSHG. The seminar started with a technical talk entitled “The most comprehensive view of the human genome with PicBio SMRT(r) sequencing” by Dr. Caroline Chan from Pacific Biosciences. The talk was followed by three research presentations: (i) ‘Hemotopoietic stem cell biology as a fundamental niche in hematotoxicology: Benzen as a model’ by Dr. Zariyantey Abd. Hamid of the National University of Malaysia (UKM) (ii) ‘The role of TERT, TERC and telomerase activity in chronic myeloid leukaemia patients: research experience’ by Dr. Sarina Sulong of Universiti Sains Malaysia and (iii) ‘Preliminary overview of Senoi from G6PD and Thalassemia analysis) by Danny Koh Xuan Rong of the National University of Malaysia (UKM). The program started with opening remarks by Prof. Zilfalil Alwi and ended concluded with the Annual General Meeting (AGM) at mid-afternoon. Participants of the Seminar on Human Genetics 2016 in Kuala Lumpur, Malaysia.

| The Photo Diary is on page 8

MyHVP Newsletter | June 2016 | page 3


When a Geneticist Writes Exploring the Human Oral Microbiome Prepared by: Dr. Nik Norliza Nik Hassan

School of Health Sciences, Universiti Sains Malaysia, Kubang kerian and a Member of MyHVP

By

history, Antony van Leeuwenhoek was the scientist who reported the oral bacteria as among the first microorganisms that have been described on earth. Following the descriptions of the animalcules in 1676 from scrapings of teeth and the development of agar-containing solid culture media for the growth of bacteria, has allowed the identification of many pathogens of human and periodontitis came under study. The flow of the research however, was a bit disappointed as only a few bacteria were able to be cultured and small portions could be seen microscopically. Thus, that time it was concluded that no specific bacteria species were responsible for the disease. The oral cavity is a major gateway to the human body. Microorganisms colonizing one area of the have a significant probability of spreading on contiguous epithelial surfaces to neighboring sites. Microorganisms from the oral cavity have been shown to cause a number of oral infectious diseases, including caries (tooth decay), periodontitis (gum disease), endodontic (root canal), infections, alveolar osteitis (dry socket) and tonsillitis. Accumulated evidence that links oral bacteria to a number of systemic diseases including cardiovascular (Preza et al., 2008), stroke (Joshipura et al., 2003), preterm birth (Offenbacher et al., 1998), diabetes (Genco et al., 2005) and pneumonia (Awano et al., 2008). Many studies have been reported on the classification and identification of the microorganisms related to the human oral. Rosebury et al (1950) performed detailed anaerobic studies on the gingival scrapings and discovered diverse community of microbiota. However, they concluded that periodontal disease was caused by unknown factors but once initiated, the condition triggered the proliferation of the normal microbiota further exacerbating the disease process. In 1977, Newman and Socransky reported a group of Gram-negative facultative anaerobes such as Actinobacillus showed to be associated with wide range of clinical infections such as pulmonary, cardiovascular and soft tissues infections. There are many difficulties in using culture to characterized periodontal microbiota. Anaerobic bacteria which are predominate the habitat are typically slow growing and nutritionally fastidious. Identification via biochemical and physiological tests requires expertise and time consuming. These constraints place a severe limitation on the number of samples that can be processed. For the reasons mentioned, alternative methods are urgently needed that able to provide reliable and high-throughput diagnostic tool to increase the depth of understanding of the role of oral microbiota in initiating human diseases. Studies have proved that without fully understanding the collective microbiome or human superorganism, it is impossible to dissect the human health and disease. These have proved by molecular analyses findings that DNA/ RNA-based approaches have revealed enormous variation in the microbiome of diverse environments, including the human body

(Ecburg et al., 2005, Grice et al., 2008, Wade, 2011). A strength of the 16S rRNA gene PCR/ cloning/sequencing technique is that the PCR primers can be designed to be specific for particular group of interest. The approaches have built on the body of work available from culture based studies and led to the development of the Human Oral Microbiome Database (HOMD). Human Oral Microbiome Database (HOMD) and is accessible via www.homd.org. The microorganism found in the human oral cavity recently known as oral microbiome comprised of over 600 prevalent taxa at the species level, with distinct subsets predominating at different habitats. It has been extensively characterized by cultivation and culture-independent molecular methods such as 16S rRNA cloning. The term ‘microbiome’ was coined to signify the ecological community of commensal, symbiotic and pathogenic microorganisms that literally share human body space and ignored as determinants of health and diseases (Lederberg & Mccray, 2001). Paster and coworkers have proved that 16S rRNA gene- based molecular cloning methods, have largely replaced cultivation studies. In 2001, they have identified approximately 280 bacterial species from the oral cavity studies. The partial 16S rRNA sequence have produced global patterns of diversity in microbiome in human salivary (Nasidze et al., 2009). By comparing the data to the RDPH database, a total of 101 bacterial genera including 39 that has not been previously described from the human oral cavity have been reported. Dewhirst and coworkers (2010) have collected a 16S rRNA gene sequences into a curated phylogeny-based database (HOMD). In conclusion,16SrRNA molecular based studies have revealed the hidden diversity of the microbial world. References 1. Ass, J., Paster, BJ., Stokes, LN., Olsen, I and Dewhirst, FE. 2003. Defining the normal bacterial flora of the oral cavity. J. Clin Microbiol. 43: 5721-5732 2. Eckburg, PB., Bik EM., Bernstein, CN., Purdom, E., Dethlefsen, L., Sargent, M., Gill, SR., Nelson, KE., and Relman, DA. 2005. Diversity of the human intestinal microbial flora. Science. 308: 1635-1638 3. Grice, EA., Kong, HH., Renaud, G., YToung, AC, Bouffard, GG., Blakesley, RW., Wolfsberg, TG., Turner, ML., and Segre, JA. 2008. A diversity profile of the human skin microbiota. Genome Res. 18: 1043-1050 4. Lederberg, J and AT Mccray. 2001. ‘Ome sweet omics- a geneaological treasury of words. Scientists. 15: 8-10 5. Paster, BJ., SK Boches, JL., Galvin, RE., RE. Ericson, CN., Lau, VA., Levanos, A. Sahasrabudhe and FE. Dewhirst. 2001. Bacterial diversity in human subgingival plaque. J. Bacteriol. 183: 3770-3783 6. Nasidze, I., Li, J., Quinque, D., Tang., K., and Stoneking, M. 2009. MyHVP Newsletter | June 2016 | page 4


When a Geneticist Writes 7. 8. 9. 10. 11. 12. 13. 14. 15.

Global diversity in the human salivary microbiome. Genome Res. 19: 636-643 Dewhirts, FE., Chen, T., Izard, J., Paster, BJ., Tanner ACR., Yu, W., Lakshmanan, A., and Wade, WG. 2010. The Human Oral Microbiome. J. of Bacteriol. 92 (19): 5002- 5017 Awano, ST., Ansai, Y., Takata, I., Soh, S., Akifusa, T., Hamasaki, A., Yoshida, K., Sonoki, K, Fujisawa, K., and Takehara, T. 2008. Oral health and mortality risk from pneumonia in the elderly. J. dent Res. 87: 334-339 Genco, RJ., Grossi, SG., Ho, S., Nishimura, F., Murayama, Y. 2005. A proposed model linking inflammation to obesity, diabetes and periodontal infections. J. Periodontal. 76: 2075-2084 Joshipura, KJ., Hung, HC., Rimm, EB., Willett, WC., Ascherio, A. 2003. Periodontal disease, tooth loss and incidence of ischemic stroke. Stroke. 34: 47-52 Offenbacher, S., Jared, HL., O’Reilly., PG., Wells, SR., Salvi, GE., Lawrence, HP., Socransky, SS., and Beck., JD. 1998. Potential pathogenic mechanism of periodontitis associated pregnancy complications. Ann. Per iodontal. 3: 233-250 Preza, D., Olsen, I., Aas, JA., Willumsen, T., Grinde, B., Paster, BJ. 2008. Bacterial profiles of root caries in elderly patients. J.Clin Microbiol. 46: 2015-2021 Wade, WG. 2011. Has the use of molecular methods for the characterization of the human oral microbiome changed our understanding of the role of bacteria in the pathogenesis of periodontal disease? J. Clin. Periodontal. 38 (11): 7-16 Rosebury, T., MacDonald, JB., Clark, AR. 1950. A bacteriologic survey of gingival scrapings from periodontal infections by direct examination, guinea pig inoculation and anaerobic cultivation. J. of Dental Res. 29: 718-731 Newman, MG & Socransky, SS. 1977. Predominant cultivable microbiota in periodontitis. J. of Periodontal Res. 12: 120-128

HVP Global Sabbatical @Centre for Translational Pathology, University of Melbourne Prepared by Dr. Muhammad Farid Johan

School of Medical Sciences, USM Health Campus and a Member of MyHVP

The

University of Melbourne consistently ranks among the leading universities in the world, with international rankings of world universities placing it at number 1 in Australia and number 33 in the world (Times Higher Education World University Rankings 2015-2016). The university has seven campus locations across Melbourne, including the Parkville campus where the medical building is located. It was, therefore, a privilege to be attached to the Centre for Translational Pathology, Division of Department of Pathology, the University of Melbourne, Parkville, Victoria, Australia for a 3-month sabbatical leaves in 2015. The Centre for Translational Pathology aims to assist in the translation of research discoveries and inventions into new diagnostic products and services for patients. The centre runs the translational research laboratories and translational genomics facility that offers a broad range of diagnostic screens for neurodegenerative diseases and analyses for somatic mutation detection, done through the acquisition of an Illumina HiSeq2500 and MiSeq. It was also a privilege to be supervised by Professor Graham Taylor, who leads the Translational Genomic laboratory, the Herman Professor of Medical Genomics. Professor Taylor is regarded as the preeminent UK scientist in implementing genomic technology in a healthcare research and service setting. He was the past president of the Human Variome Society and the Director of the HVP Australia node.

One of the sabbatical on-site experiences was the observation of the application of the 4-step IThe Illumina NGS workflow - library preparation, cluster generation, sequencing and data analysis. The sequencing of 28 genes for neurogenetic tests, five genes for cancer tests and 12 genes for molecular pathology tests are done in Illumina HiSeq and MiSeq at the centre. One of the activities in the Translational Genomic laboratory is variant curation that includes classification of germline DNA variants in the mutation detection services. The interpretation of sequence variants is based on the recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology. These ACMG Standards and Guidelines help to provide quality clinical laboratory services. Adherence to these standards and guidelines is however voluntary and does not necessarily assure a successful medical outcome. The ACMG Standards and Guidelines has provided a set of criteria classifying sequence variants into ‘Pathogeneic’, ‘Likely pathogenic’, ‘Benign’, ‘Likely benign’, and ‘Uncertain significance’. | See page 6

MyHVP Newsletter |June 2016 | page 5


HVP Global | Continued from page 5

The thoroughness with which the team at The Centre for Translational Pathology, University of Melbourne conducted their interpretation of the When classifying and reporting a variant, information in databases and sequence variants is commendable. As such, I would like to recommend published literature are found to be valuable. The population databases that adherence to the ACMG Standards and Guidelines be introduced to such as dbSNP and dbVar are useful in obtaining the frequencies of vari- the genetics and molecular laboratories in our centers. ants in large populations. On the other hand, the disease databases such as ClinVar and OMIM primarily contain variants found in patients with Dr Muhammad Farid Johan disease and assessment of variants’ pathogenicity. In addition, when in- Department of Haematology terpreting the sequence variants, in silico tools, either publicly or com- School of Medical Sciences mercially available are also of a great value. These includes the missense Universiti Sains Malaysia prediction, splice site prediction and nucleotide conversion prediction Kubang Kerian, KELANTAN. software programs. Table 1: Some useful tools/softwares dbSNP dbVar 1000 Genomes Project ClinVar

http://www.ncbi.nlm.nih.gov/snp http://www.ncbi.nlm.nih.gov/dbvar http://browser.1000genomes.org http://www.ncbi.nlm.nih.gov/clinvar

OMIM Human Gene Mutation Database Human Genome Variation Society NCBI Genome ConSurf MutationAssessor

http://www.omim.org http://www.hgmd.org http://www.hgvs.org http://www.ncbi.nlm.nih.gov/genome http://consurftest.tau.ac.il http://mutationassessor.org

GeneSplicer PhastCons

http://www.cbcb.umd.edu/software/GeneSplicer/gene_spl.shtml http://conpgen.bscb.cornell.edu/phast/

References

The University of Melbourne website: http://www.unimelb.edu.au Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 17(5):405-24.

MyHVP Newsletter | June 2016 | page 6


Postgraduate The potential role of epigenetic in alternative therapy of β-thalassemia Haiyuni Mohd Yassim, Wan Zaidah Abdullah and Muhammad Farid Johan

School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan & MyHVP member ‘Epigenetic marks persist during development and are potentially be transmitted to offspring in which generating the large range of different phenotypes that arise from the same genotype’ (Portela & Esteller, 2010).

Aberrant

modification of epigenetic may lead into several diseases such as cancer, autoimmune disorder and genetic disease. Epigenetic is one of the molecular mechanisms that are fundamental in the regulation of many cellular processes, involving gene and microRNA expression, DNA-protein interactions, cellular differentiation, suppression of transposable element mobility, embryogenesis, X-chromosome inactivation and genomic imprinting. In this advanced technology, epigenetic modification is considered as one of the clinical therapies mainly used in cancer patients and also as a potentially lead to novel therapeutic in hemoglobinopathies such as β-thalassemias. β-thalassemias are the most common genetic disorders in hereditary anemia that cause considerable morbidity and mortality throughout the world including Malaysia. Sickle cell Disease (SCD) and HbE/β-Thalassemia results from qualitative abnormalities whereas β-thalassemia is due to quantitative abnormalities of the adult β-globin chain. Both lead to decreased life span of red cells, increased haemolysis and ineffective erythropoiesis. Epigenetic modifications may result in the changing of gene expressions and functions without corresponding alteration in DNA sequence. The epigenetic modification can be grouped into three main categories which are DNA methylation, histone modification and nucleosome positioning. DNA methylation mostly occurs in the context of CpG dinucleotides in which presence in cluster regions known as CpG islands. Generally, methylation at CpG islands is associated with gene silencing in which DNA methyltransferases (DNMTs) promoting the binding of a methyl group in the 5’ position of cytosine residues in a CpG dinucleotides. On the other hand, histone modification occurs when the lysine residues are introduced to the N -terminal tails of histones. This will be subjected to several post-trascriptional modifications including acetylation, methylation, phosphorylation and ubiquitination that can influence the chromatin structure. The acetylation of lysine residues regulated by histone acetyltransferases (HATs) promotes an open conformation of chromatin with activation of gene expression while the deacetylation promotes a close conformation with repression of gene expression by histone deacetylases (HDACs). Activation of gene expression can be determined by high levels of H3K4me3, H3K27ac, H2BK5ac and H4K20me1 in the promoter and H3K79me1 and H4K20me1 along the gene body. Gene expression can also be regulated through nucleosomes positioning in which nucleosomes acts as a barrier to transcription that blocks access of activators and transcription factors to their sites on DNA and inhibit the elongation of the transcription by engaged polymerases affecting the transcription process.

tiation. Furthermore, LARP2 gene has a protective effect in histone deacetylase (HDACs) and the expression level of HDAC3 can influence the expression of the transcription status of locus control regions (LCR) sequences that are crucial for β-globin to reach these exceptionally high transcription rates. Therefore, the hypermethylation of LARP2 gene caused down-transcription reducing the production of β-globin. Moreover, DNA hypomethylation and histone acetylation were reported to be effective in the induction of γ-globin expression which may have reduced the severity of symptoms among Thalassemia patients (Ahmadvand et al., 2014). In SCD, a high level of HbF would interfere with the polymerization of HbS and prevent sickling of red blood cells. On the other hand, in β-thalassemia, a high level of β-globin chain synthesis would decrease non-α:α chain imbalance and improve the anemia. DNA methylation results in changes in chromatin structure and enhances the binding of transcription factors, leading to de-repression and transcriptional activation of γ-globin gene expression in adult life. Several hypomethylation agents have been introduced to stimulate the production of HbF including 5’azacitidine and decitabine. The use of thalidomide and sodium butyrate also promotes the induction of γ-globin. Thalidomide increases H3K4 methylation in γ-globin gene promoter and decreases H3K27 methylation. Butyrate induces dissociation of histone deacetylase inhibitor 3 (HDAC3) in chromatin level to induced γ-globin gene expression. Based on the results, the increase of H3K4 methylation by thalidomide was the highest compared to sodium butyrate and combination of both agents (p<0.05). This shows that thalidomide is more effective in alteration of methylation effect. In conclusion, methylation of the promoter of the several genes in thalassemia such as LARP2 gene and γ-globin gene play important roles in the occurrence and amelioration of the effects of Thalassemia. Taking this into account, treatment strategies considering epigenetic mechanisms may serve as an innovative therapy for this genetic disease. References Ahmadvand, M., Noruzinia, M., Dehghani Fard, A., Montazer Zohour, M., Amin Tabatabaiefar, M., Soleimani, M., Saki, N. (2014). The role of epigenetics in the induction of fetal hemoglobin: A combination therapy approach. International Journal of Hematology-Oncology and Stem Cell Research, 8(1), 9–14. Gao, T., Nie, Y., & Guo, J. (2012). Hypermethylation of the gene LARP2 for noninvasive prenatal diagnosis of β-thalassemia based on DNA methylation profile. Molecular Biology Reports, 39(6), 6591–6598.

This review highlights the role of epigenetics in diagnosis and provision of potential alternative therapy for β-Thalassemia. It was reported that the hypermethylation of LARP2 gene is one of the potential mechanism in epigenetics for diagnosis of β-thalassemia. The results showed that the DNA methylation of LARP2 was hypermethylated in β-thalassemia when compared with the normal blood (Gao et.al, 2012). LARP2 (La ribonucleoprotein domain family, member 1B) gene is an important component of ribonucleoprotein complexes which function mainly as an RNA domain (CTD), facilitating correct processing and maturation of RNA polymerase III transcripts in stimulating the translation iniMyHVP Newsletter |June 2016 | page 7


Photo Diary Key events in the first half of 2016 All photograps below were taken during January - June 2016

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Seminar on Human Genetics in conjunction with Annual General Meeting of MSHG 2016

HUGOâ&#x20AC;&#x2122;s Human Genome Meeting 2016

Knowledge Program with National Council of Professor (MPN) with Terengganu Communities

Sixth Biennial Meeting of the Human Variome Project Consortium

25 February 2016

28 Feb - 2 March 2016

26 - 27 May 2016

30 May - 3 June 2016

Universiti Malaya, Kuala Lumpur Malaysia

Houston, USA

Terengganu, Malaysia

UNESCO Headquarters, Paris, France MyHVP Newsletter | June 2016 | page 8

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