Abstract
Select Biosciences held its annual Genomics Research Asia 2012 Conference in the city of Daejeon, Republic of Korea, on 13–14 November 2012. This conference brought together an international roster of speakers and delegates primarily from Korea, but also from other parts of Asia, North America and Europe. The conference consisted of two tracks: first, RNAi, miRNA and epigenetics; and second, next-generation sequencing and advances in quantitative PCR. In this conference scene article, I report on selected presentations delivered in the RNAi, miRNA and epigenetics conference track and frame them into the broader trajectory adopted by these spaces.
The fields of RNAi, miRNA research and epigenetic research are rapidly expanding, largely driven by the translational opportunities in therapeutics development and biomarker discovery and deployment. For this reason, there is extensive interest across Asia in the deployment of various molecular biomarker classes for developing novel diagnostics, such as for infectious disease, as well as cancer. The interest in miRNAs is driven in large part by the realization that a large number of diseases – primarily cancers – are associated with dysregulated miRNA expression patterns of note present in biological fluids, such as the blood. In this manner, the capture and analysis of miRNAs from biological fluids can provide an insight into the disease processes precipitating in vivo.
Another area where there is extensive basic and translational research is epigenetics. In this context, it is important to note that many cancers are associated with not only genomic modifications and chromosomal alterations but also epigenetic changes in vivo, such as epigenetic silencing of tumor suppressor genes. Therefore, there is much interest in discovering epigenetic profiles, not only for basic discovery efforts but also as biomarkers for disease, especially cancer.
Finally, the third vignette presented in this conference track was focused on RNAi therapeutics. The targeting of mRNA species in vivo to modulate their expression for therapeutic purposes using RNAi promises to open up the potential targeting of the entire genome, not just the 10–20% of the protein-coding genes that are currently targetable using small molecules or biologics (‘the druggable genome‘). However, this hope has been met with significant empirical obstacles primarily relating to the delivery of the RNAi therapeutic entity to the proper target organ in vivo, and the reduction of associated off-target effects. The industry expects to address these issues over this decade such that we may see the emergence of RNAi-based therapeutics in the clinic over the next decade.
Epigenetics: the final frontier in genome modulation
Sungwhan An (President & CSO, Genomictree, Inc., Daejeon, Republic of Korea) presented a talk entitled ‘Discovery of SDC2 gene as a methylation biomarker and utility test in serum DNA for earlier detection of colorectal cancer (CRC).‘ This company is focused on discovery circulating biomarkers that are methylation-based as a means for minimally invasive detection of early-stages of CRC. An stated that CRC develops as a result of the progressive accumulation of genetic and epigenetic alterations resulting in the transformation of normal colonic epithelium to colon adenocarcinoma. If DNA methylation takes place at early stages during the transformation process, and if the same sites are methylated across many CRC patients, then this methylation can serve as a biomarker for the early detection of CRC.
An and colleagues discovered differential methylation in the SDC2 CpG region through verification in match-paired colorectal tissues from CRC patients. They further demonstrated that the differential methylation of the SDC2 CpG locus is observed in serum DNA samples from CRC patients via quantitative PCR. After surgical resection of the colon tumors, the levels of methylated SDC2 decreased, suggesting that this epigenetic marker is a prognostic marker of CRC, and furthermore, this biomarker can be harvested from serum samples from patients suggesting its potential utility as a screening biomarker.
Edwin Cheung (Department of Cancer Biology and Pharmacology, Genome Institute of Singapore, Biopolis, Singapore) presented a talk entitled ‘Genomic analyses of hormone signaling and gene regulation.‘ The focus of this talk was on elucidating the mechanism of transcriptional regulation by the estrogen receptors (ERs). Specifically, whether such a mechanism involves chromatin remodeling. Cheung showed that the majority of ER binding sites are located far away from the transcription start sites of genes, suggesting the possibility that ERs can mediate long range chromatin interactions – that is, chromatin remodeling. The data presented showed that interactions can range from 10 kb to 1 Mb in distance.
Long range chromatin interactions are associated with transcriptional regulation. Most genes located in the ‘anchor‘ regions of these chromosomal loops are in a transcriptionally active state, whereas those genes located in the ‘loop‘ regions of these chromosomal loops are in a transcriptionally inactive state. In summary, ERs can mediate over 1000 long range chromatin interactions and the majority of these interactions are intrachromosomal. These long range chromatin interactions may have significance in normal transcriptional control and may be perturbed in diseases such as breast cancer.
Sung Hee Baek (Seoul National University, Republic of South Korea) presented a talk entitled ‘Chromatin dynamics and epigenetic regulation in cancer‘. Dr Baek studied metastasis suppressor genes – genetic elements that do not have an influence on the growth of the primary tumor but block metastasis. One such gene is KAI1. KAI1 functions as a metastasis suppressor gene as assessed by in vivo metastasis assays. Expression of KAI1 significantly suppresses the in vivo incidence of lung metastases without affecting the primary prostate tumor in an experimental model system.
In the second part of her presentation, Baek addressed the issue of the ‘chromatin code‘ versus merely the ‘histone code.‘ The chromatin code is an ensemble of DNA methylation, histone modifications and other higher-order chromatin changes. In this manner, it is highly informative and predictive of chromatin structure and dynamics in the native state. This work is important as it seeks to establish rules determining gene activation or silencing via epigenetic means and this may be significant in disease states in vivo.
miRNAs: genomic elements with prognostic & therapeutic value
Tsuyoshi Yokoi (Drug Metabolism and Toxicology, Kanazawa University, Japan) presented a talk entitled ‘Regulation of human nuclear receptors and cytochrome P450s by miRNAs.‘ The focus of this talk was on miRNAs targeting drug-metabolizing enzymes. Many members of the cytochrome P450 class of enzymes are modulated by miRNAs such as miR-27b, -378, -125b, -24, -17 and -133a, among others. These data suggest a translational repressive role of miRNAs in the regulation of drug-metabolizing enzymes and suggest means by which drug levels in vivo during pharmacologic administration may be modulated by specific miRNAs.
Yokoi also discussed the concept of circulating miRNAs that are perhaps enveloped in exosomes or microvesicles. Indeed, plasma miRNAs may be markers of liver injuries. Yokoi suggested several miRNAs such as miR-122, -101a, -130a and -206, among others, which may serve as circulating biomarkers of liver cirrhosis. In summary, not only are miRNA expression patterns tightly coupled to cancer but also to many other physiological and pathological processes in vivo and therefore, can be utilized as prognostic biomarkers.
Keitaro Hagiwara (Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan) presented a talk entitled ‘Mechanisms of miRNA regulation by natural products and their therapeutic potential for human cancer.‘ The focus of this presentation was on the natural product resveratrol, which has been shown to increase miR-200c expression – a tumor-suppressive miRNA. Resveratrol suppresses tumor invasion in vitro assays and it specifically reduces the cancer stem cell fraction in tumors. Resveratrol has also been shown to inhibit tumor formation in vivo and it upregulates E-cadherin expression. Importantly, resveratrol has been shown to upregulate the levels of tumor-suppressive miRNAs. Taken together, these results show that natural products may be deployed for the modulation of the miRNA pathway in vivo and this may be harnessed for therapeutic benefits.
RNAi-based therapeutics
Jeiwook Chae (Head of Therapeutic R&D, Bioneer Korea) presented a talk entitled ‘SAMiRNA™ nanoparticle RNAi prodrug technology.‘ Bioneer is a company developing next-generation platform technology for sequence-based therapeutics and molecular diagnostics. SAMiRNA™ stands for ‘self-assembled micelle inhibitory RNA,‘ which requires no formulation. In other words, there is a solid-phase synthesis of these siRNA conjugates with no encapsulation required. At a critical micelle concentration, SAMiRNA spontaneously forms nanoparticles. These nanoparticles are then designed to target tumors specifically. Bioneer is focusing on a number of therapeutic areas utilizing this RNAi therapeutic platform technology. It remains to be seen at this point if this technology would address the persisting problems of ‘targeted delivery to specific tissues‘ that have plagued the RNAi therapeutics field from the start.
Dmitry Samarsky (EVP, Technology & Business Development, RiboBio Co., Guangzhou, China) presented a talk entitled ‘RNAi and antisense oligonucleotide in vivo delivery for therapeutic applications.‘ Samarsky discussed a number of different methodologies for mediating the process of RNA interference in vivo. There are unformulated RNAi species composed of chemically modified or conjugated RNAi molecules. Another segment of this marketplace is the delivery vehicle formulated species wherein liposomes, dendrimers, polymers, cationic lipoplexes or nanoparticles are utilized to effect delivery. It is currently believed that no one methodology is applicable for delivery to all organs and most likely, in the future, RNAi-based therapeutics will be composed of many different approaches – both formulated and unformulated. There is also the concept of single-stranded versus double-stranded RNAi therapeutics molecules.
In summary, the RNAi therapeutics field is littered with different technology platforms that have been developed and proposed to offer solutions to the delivery problem. We believe that the ultimate suite of technologies for RNAi therapeutics must scale to address almost every genomic element in vivo that needs to be therapeutically modulated/targeted.
Future perspective
Genomics Research Asia 2012 in Korea focused on bringing together primarily academic researchers in a cross-disciplinary conference where academic researchers and industry-focused researchers, as well as exhibiting companies find a common venue for the exchange of ideas and forging of collaborations. There is extensive growth across Asia in companion diagnostics, biomarker research, translational research and epigenetic-focused research efforts. Given the fact that researchers in Asia have deep ties with North American and European research institutions, we expect this type of conference to be highly conducive in the formation of collaborations, partnerships and joint ventures in the coming years.
Financial & competing interests disclosure
E Razvi declares that he authors market reports, provides strategic consulting and advises companies around the world in the life sciences space, including companies in Asia/Pacific in the RNAi, miRNA and epigenetics areas. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.