HAYATI Journal of Biosciences xxx (2016) 1e4

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Review article Proteogenomics: New Emerging Technology

* Wasim Sajjad,1,2 Muhammad Rafiq,3 Barkat Ali,3 Muhammad Hayat,3 Sahib Zada,3 Wasim Sajjad,3 Tanweer Kumar4

1 Key Laboratory of Petroleum Resources, Gansu Province/Key Laboratory of Petroleum Resources Research, Institute of Geology and Geophysics, Chinese Academy of Sciences, Lanzhou, PR China. 2 University of Chinese Academy of Sciences, Beijing, PR China. 3 Department of Microbiology, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan. 4 State Key Laboratory of Grassland Agro-ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, PR China. article info abstract

Article history: The term proteogenomics is basically the integration of with and transcriptomics. Received 7 June 2016 Today, proteogenomics is developing on the way to combined understanding about overall cellular Received in revised form functions. At present globally, structure of , expression of genes (in the form of mRNA synthesis), 5 November 2016 synthesis of proteins (translation of mRNA) and post-translational modification (structural modification Accepted 11 November 2016 of proteins) have turn out to be technically practicable and act as a novel viewpoint to molecular pro- Available online xxx cedures. Current research has proved the importance of proteogenomics technology in cancer for studying molecular signature of tumors particularly in human beings, and its treatment and prevention. KEYWORDS: genomics, Proteogenomics is not restricted to oncology but it also plays a vital role in other areas of life sciences and , biomedicines and anticipation can make up these areas. Here in this minireview, we will discuss the proteomics, latest progress made in recent years, challenges and viewpoints about proteogenomics technology. proteogenomics, Copyright © 2016 Institut Pertanian Bogor. Production and hosting by Elsevier B.V. This is an open access transcriptomics article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction biased and non-targeted manner. This can also be extended to high-dimensional biology which includes integration of these “Omic” technologies such as genomics, transcriptomics, prote- techniques called system biology (bio-based research that focus on and metabolomics are high-throughput approaches which the systematic study of multipart relations in biological systems by significantly increase the number of genes/protein that can means of integration models; Westerhoff and Palsson 2004; Kell concurrently detect and successfully link complex mixtures to 2007). “Omic” technologies not only are applied for better under- multipart effects in the system of /protein expression profile. standing of normal physiological processes but also play a vital role These technologies analyze and characterize biological system into in screening, diagnosis, prognosis and understanding of etiology of unknown details of ten thousands of genes and proteins simulta- diseases (Horgan and Kenny 2011). These approaches are being neously. Application of this “omic” technologies changed the successfully used in (interaction of genomics application pattern of this complex blend in field of medicine and and pharmacology) for discovery of drugs and their toxicity and opened several new fields (Ulrich-Merzenich et al. 2007). These efficacy assessment (Kell 2006). technologies deal with the molecules that are integral parts of the The term genomics was used by Tom Roderick that meant to cell, tissue or organism. “Omic” technologies include analysis and analyze the entire genome. Today, it generally refers to high- characterization of genomics (deals with genes), transcriptomics throughput, large-scale investigation of multiple genes and prod- (deals with mRNA), proteomics (deals with proteins) and metab- ucts or region of genes (Cook-Deegan et al. 2000). The term geno- olomics (deals with metabolites) in a biological sample in a non- mics covered the area of genetics that deals with genome sequencing and analysis of an organism. It is the whole DNA content that is present within one cell of an organism. The term * Corresponding author. Key Laboratory of Petroleum Resources, Gansu Province/ was used by Wilkins et al. (1995,1996). Proteomics is a quickly rising Key Laboratory of Petroleum Resources Research, Institute of Geology and approach within molecular biology that deals with the organized, Geophysics, Chinese Academy of Sciences, Lanzhou 730000, PR China. high-throughput methodology toward the analysis of protein E-mail address: [email protected] (W. Sajjad). expression, structure and function within a cell or an organism Peer review under responsibility of Institut Pertanian Bogor. http://dx.doi.org/10.1016/j.hjb.2016.11.002 1978-3019/Copyright © 2016 Institut Pertanian Bogor. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Sajjad, W., et al., Proteogenomics: New Emerging Technology, HAYATI J Biosci (2016), http://dx.doi.org/ 10.1016/j.hjb.2016.11.002 2 W. Sajjad, et al

(Theodorescu and Mischak 2007). Typical results of proteomics 1959). However, genomes of several organisms have been studies are inventories of the protein content of differentially sequenced successfully but researchers are struggling for the entire expressed proteins across multiple conditions (Silva et al. 2006; proteome characterization. Human proteome first draft has been Boersema et al. 2015). After accomplishment of human genome described recently (Kim et al. 2014) but complete description is still project and some other model organisms, has not only given us high awaiting, and the basic complexity source seems to be the protein throughput evidence about DNA and organization of genes, but also compartmentalization in organ and tissue. In human body there are unlocked the means for gene expression investigation (Merrill et al. around 200 types of cells, which are structured into tissues and 2006; Bendixen et al. 2010). On the basis of such information, then organs, therefore, forming a diversity of . Therefore, transcriptomics has increasingly grown from very simple investi- it is going to be challenging to define the human and other species gation of discrete transcript levels with the help of microarray to the proteomes and will need high contact of international coordination synchronized sequencing of entire that are expressing in living and efforts. cells. Therefore, the combination of genomics and transcriptomics Practically, proteomic examination of living body is now which is called , can lead us toward better un- promising because their genome sequences are now online avail- derstanding of the connection between phenotypes and genotypes, able for online investigation (Tyers and Mann 2003). Following and brought a revolution in the fields of medicine and modern breakdown of protein extract, the fragments of resul- biology. Presently, both genomics and transcriptomics summaries tant proteins are evaluated in and the obtained have been recognized for so many pathologies together with tumor, peptide sequences are further analyzed for genomic databases and which highly impacted the clinical practices for diagnosis of dis- protein identification. The genomic databases and search for ho- eases, prognosis and prediction of threats. Previously it was believed mology sequence that are identical with the data of mass spec- that the presence of gene or any phenotypic character was enough trometer are the principle of all current proteomics exploration. indicator for the gene functions. Nowadays, it is known that the Mass spectrometry has now become highly throughput and even functionality of a gene is determined by the presence of functional more sensitive for identification of protein, as demonstrated with proteins. Therefore, the requirement of the best assimilation of the shotgun proteomics (Zhang et al. 2013). It is also the main tool for functional genomics with enquiry at proteins level, the proteomics comparison and quantification of protein, and also used for the approach has increasingly arisen. These omics technologies (prote- post-translational modification determination. It must be high- omics, transcriptomics and ) can be used almost in lighted that the technology is as crucial for prote- each and every aspect of life related sciences like rapid and accurate omics as it is essential for transcriptomics and genomics disease diagnosis, rapid therapy of complex medical conditions, (Schneider and Orchard 2011). Bioinformatics technology is also diversity of an organisms in a particular habitat, mechanisms of the foundation for data assimilation from other several omics adaptation to different ecological habitats, mechanism of antibiotic technologies. resistance and also how to produce an efficient and effective vac- cines, antibiotics. Now in this review, discussion about the current 2.1. Proteogenomics development progress in mixing omics technologies, proteogenomics, and the Proteomics approach is different from genomics and tran- novel chances that unlock in life science in molecular and cellular scriptomics by two main facts. First, amplification of protein is level will be carried out. impossible because there is no technology such as polymerase chain reaction for protein amplification, so prior purification of 2. Proteomics much protein is essential for quantification and identification. Second, at the moment, no such protein arrays are present that Now it is openly understood that the amount of a specific pro- efficiently work for high throughput protein investigation. Not only tein may not be projected in sureness by the resultant mRNA. Early the antibodies are unavailable against entire proteins but also research in yeast and bacteria has recommended a sensible corre- antibody recognition and affinity change by post translational lation of approximately 50% between messenger RNA and level of modification making it difficult to carry out the protein array. proteins, but eukaryotic multicellular organisms have exposed Generally, the procedural methodologies that are used in prote- much lesser correlation (Gygi et al. 1999). In Homo sapiens, world- omics and transcriptomics are basically dissimilar and as a result wide analysis of transcriptomics and proteomics has revealed that the combination of all these omics approaches has stayed a task. just 30% of protein level changes can be described by resultant Therefore, the situation in human beings is suggestive of the mRNA variations (Vogel and Marcotte 2012). This difference challenges and difficulties. More than 20,000 genes and more than stresses the significance of post transcription regulation. The 106 proteins have 200 or more post translational modification movable translational ability of mRNA and siRNA regulation ac- types; the molecular complexity rises obviously from genomics counts the difference between mRNA transcription and proteins toward proteomics and assimilating such complexity levels needs levels partially, but splitting and proteins dynamic turnover are also an improvement in enrichment and fractionation practices involved. The half-life of proteins that ranges from few minutes to (Altelaar and Heck 2012), as well as in bioinformatics and several days is controlled by several pathways. It includes, but not computing technology (Schneider and Orchard 2011). restricted to, the proteasome and ubiquitin pathway (Claydon and The proteogenomics idea is of three stages: (1) DNA and Beynon 2012). In addition, existence and deficiency of some epigenetic regulations, (2) expression of RNA and (3) protein and its events in post translational modifications like glycosylation, post-translational modifications are concurrently examined and phosphorylation or ubiquitinylation, have great influence on sta- combined. Though this is logically seducing, currently it had not bility of proteins, and increase the level of complexity further. been implemented. In the last 2 years the situation has changed Altogether, the proteome dynamics and configuration cannot be rapidly and based on practical merging and development in bio- deduced from data of functional genomics, and consequently pro- informatics, efficient methodologies have been developed effec- teomics is crucial and corresponding methodology to both tran- tively in proteogenomics (Nesvizhskii 2014). The important step scriptomics and genomics. during proteogenomics is the synthesis of customized database of It is exciting to know that the amino acid presence and protein proteins sequences, that are obtained from genomic data and can configuration were recognized at the start of 20th century, even be further used to investigate the model of interest. Because the earlier than DNA and RNA structures were exposed (Todhunter entire genome, exome and mRNA sequencing are practicable at a

Please cite this article in press as: Sajjad, W., et al., Proteogenomics: New Emerging Technology, HAYATI J Biosci (2016), http://dx.doi.org/ 10.1016/j.hjb.2016.11.002 Proteogenomics 3 reasonable price, it is possible to explain the sequences of complete increases the current molecular taxonomy limitation exclusively theoretical proteins that are present in specific structure to be based on expression of genes, and refinement at proteomics level evaluated. It is also possible to detect proteins by means of shotgun is very exigent (Zhang et al. 2014). In general, these progresses liquid - (LC-MS/MS) indicate that proteomics is capable of delivering extra dimension against modified protein sequences database, in its place of publi- to the cancer molecular understanding (Alfaro et al. 2014), and this cally accessible generic databases. Detail description of “LC-MS/MS” could further enhance diagnostic and therapeutic approaches. technique is given in Metabolomics nrp (Metabolomics-nrp, 2006). Specifically, it should be highlighted that genomics and proteomics Eventually, this practice carries high confidence in both quantifi- investigation uses typically a reference database for modeling of cation and identification of proteins and also it offers proteins level general population, so covering patient exact deviation. Possibly, confirmation of gene expression. Therefore, this is an important the most important potential of proteogenomics for leap making achievement in molecular biology to get information from gene from bench to clinic is to offer a way for personalized investigation, level to protein and also provides the way for refinement of genes through establishment of a single patient-based customized gene and protein models. Practical challenges such as sensitivity, and proteins sequences databases. It represents clearly a vital reproducibility and accuracy in genomics and proteomics studies milestone leading to individual tumor medicine. are still present in proteogenomics analysis. Specifically, accuracy In short, these current advancements and successes in pro- and precision both in genes and proteins sequencing are perhaps teogenomics of cancer are leading us toward the investigation of the most vital concern at present time, as the error present in the other diseases in similar way and also in other fields of biology. In sequence of genes as well as in protein can be misleading the re- microbiology the proteogenomics approach has already been ports of clinical and functional studies. A special care during these implemented (Chapman and Bellgard 2014; Kucharova and Wiker processes may minimize the chances of error and misleading. 2014) also in plant sciences (Chapman et al. 2013; Castellana et al. Therefore proteogenomics eventually offer a strong source of 2014) and environmental sciences (Armengaud et al. 2013; Trapp mistake corrections both in genes and protein sequences. et al. 2014). Such studies have led to the identification and revi- sion of genes and proteins that play a significant role in funda- 2.2. Proteogenomics revolution in cancer mental physiological development, and also it helped to eliminate The advancement of proteogenomics is best shown with the ambiguous gene annotation tasks and confirmed the post research on cancer where tremendous advancement has been translational modification presence. Surprisingly, few of the achieved. Progression of cancer is carried by alteration in genome problems in these disciplines, and presence of plant and microbial and uncertainty that occurs because of cascade of genomic varia- population heterogeneity, are mutual with biology of cancer. This tion which includes , copy number aberration or trans- molecular heterogeneity, of cancer and tumor patients is basically location and (Hanahan and Weinberg 2011). Currently, a drawback of disease efficiency management in terms of threat struggles have been undertaken to define these molecular varia- deduction, analysis and treatment. So, the application of proteo- tions related with oncogenesis by sequencing the genome in more genomics throughout the life sciences will probably cause com- detail by International Cancer Genome Consortium (Hudson et al. mon enhancement and should raise its extensive usage. 2010), and The Cancer Genome Atlas project (Weinstein et al. 2013). Though, as these projects were gradually developed, now it is obvious that association of cancer genotype and phenotype also 3. Future guidelines and conclusion needs the cancer proteotype description. Developments in high throughput proteomics (such as shotgun proteomics) enabled Though proteogenomics approach is novel progress in omics proteomics a consistent and significant methodology with abilities technology, with expected applied results in medicine and biology, of comparing those of genomics for blood sample and tumor it is quiet in beginning phase and further progress is required analysis. National Cancer Institute, in this context launched in 2011 before it become broadly adopted. First, more bioinformatics the Clinical Proteomic Tumor Analysis Consortium (CPTAC) (Ellis assimilation is needed to entirely use the complete information et al. 2013) to speed up the molecular knowledge of cancer by us- spectra acquired in genomics, transcriptomics and proteomics ing healthy, measureable, proteomic skills and workflows (Rivers studies. Second, all the outputs of proteogenomics should be et al. 2014). The main aim of CPTAC is to advance the capability to available to researchers. At current stage, more information, data- identify, treat and stop cancer by identifying proteomic markers for bases and software should be developed. Third, proteogenomics fi tumors in human. may not be the nal stage of molecular assimilation that moves Major development in CPTAC has been shown recently with a from genotype to phenotype, as we are not familiar with another main research (Zhang et al. 2014) that described proteogenomics omics technology known as metabolomics (Patti et al. 2012). The fi description of rectal and colon cancer of human. This investigation speci c metabolites synthesis by enzymatic activity will be the evaluated five proteomics subtypes in The Cancer Genome Atlas succeeding stage for well understanding of an organism, and could cohort colorectal cancer. Amazingly, 20q chromosome amplicon also be assimilated into proteogenomics technology. In short, there was linked with the prime universal alteration at mRNA and pro- are more and more combined challenges present and the future of teins level and data from proteomics showed 20q candidate tar- medicine and biology is possibly somehow different. gets and biomarkers for colorectal cancer therapy. The results also showed that mRNA transcript quantity did not make reliable Acknowledgements prediction about protein quantity variance between cancers. It is noteworthy that cancer taxonomy made so far totally depends on The authors wishes to acknowledge the financial support from genomics and transcriptomics examination. For example in breast The “World Academy of Sciences (TWAS)”, provided in TWAS cancer there are four chief classes of cancers which are luminal A, president-fellowship program 2015. luminal B, triple negative/basal and HER2 that have been identified based on genes expression and this taxonomy is updated frequently by adding subclasses (Dawson et al. 2013), specifically Conflicts of Interest in terms of treatment response. Low connection demonstration between messenger RNA and protein quantity in colorectal cancer The authors declare no conflict of interest.

Please cite this article in press as: Sajjad, W., et al., Proteogenomics: New Emerging Technology, HAYATI J Biosci (2016), http://dx.doi.org/ 10.1016/j.hjb.2016.11.002 4 W. Sajjad, et al

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Please cite this article in press as: Sajjad, W., et al., Proteogenomics: New Emerging Technology, HAYATI J Biosci (2016), http://dx.doi.org/ 10.1016/j.hjb.2016.11.002