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Q&A: Ghasem Hosseini Salekdeh on Iran's Role in the Chromosome-Centric Human Proteome Project

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Name: Ghasem Hosseini Salekdeh
Position: Head of Department of Systems Biology, Royan Institute; President, Iranian Proteomics Society
Background: PhD, International Rice Research Institute, Philippines; Head of Physiology and Proteomics Department, Agricultural Biotechnology Research Institute of Iran

The Human Proteome Organization's Chromosome-Centric Human Proteome Project, or C-HPP, officially launched this month at the organization's 11th annual meeting in Boston.

The project, which is slated to extend over ten years and two phases, brings together 24 international teams with the aim of characterizing the proteome of each human chromosome (PM 9/14/2012).

Ghasem Hosseini Salekdeh is the leader of the Iranian C-HPP initiative, which is focused on characterizing the proteins of the Y chromosome. He spoke this week to ProteoMonitor about Iran's work on the initiative and proteomics research in the country more generally.

Below is an edited version of the interview.

How did Iran become involved in the C-HPP, and why did you select the Y chromosome for your portion of the study?

The Iranian Proteomics Society was established in 2004, and, in fact, I have been part of the Asia Oceania Human Proteome Organization council since 2004. So we have a good connection with the international society including the AO HUPO and also HUPO, and we were informed about the C-HPP from the beginning. Korea picked chromosome 13, and then Russia picked chromosome 18, and Iran was the third country, [and we] picked chromosome Y.

The reason [for picking the Y chromosome] was that… during the second year of the Iranian Proteomics Society Conference in Tehran [in 2009], we invited the president of HUPO at that time, Professor Young-Ki Paik. At that time the C-HPP had not been launched officially, and during this conference, [Paik] gave a presentation about the C-HPP and also suggested that, since Iran has the largest male infertility treatment clinic in the Middle East, and that some important genes related to male infertility are located on the Y chromosome, [that the country work on the Y chromosome]. Since we have, in fact, interest in the treatment of male infertility and we already have some departments involved in research in male infertility, we decided that we would pick the Y chromosome so that we would have enough funding to support this project, and it would be in line with our major [national] objective of treating male infertility.

So by choosing the Y chromosome you had a better chance of getting funding given the country's interest in research into male infertility?

Yes, in fact I am working at the Royan Institute [for Reproductive Biomedicine, Stem Cell Biology and Technology], and the Royan Institute has the largest male infertility clinic in the Middle East. The Royan Institute is the major funder of the Y chromosome [project].

How long has your team been working on the Y chromosome?

We have been working on [the project] for the last two years. So first of all we made a list of all the genes and then we tried to search all available databases for any of the proteins. Then we tried to generate antibodies for some of the Y chromosome proteins, and at the same time we have started to establish a tissue bank, particularly a testes tissue bank, because most of the Y chromosome proteins are expressed in the testes. So we've established a testes tissue bank with healthy and diseased samples, which is essential for the project.

Are there any other disorders besides male infertility that you're looking at in association with your work on the Y chromosome?

Another disease that is very important for us is prostate cancer. Two major diseases related to the Y chromosome are prostate cancer and male infertility. So we are actually putting an emphasis on these two diseases. But there are some other diseases also related to the Y chromosome that we may become involved with in the later stages of the project.

How far along is the research?

The number of unique proteins on the Y chromosome is very limited – it's only about 27 or 28 unique proteins — but of course there are some isoforms that we need to look at in the next phase of the project. But for the time being our major target is 25 proteins on the Y chromosome, and so far we have generated antibodies to almost two-thirds of these proteins, and we hope that in the next six months we will generate [antibodies to] almost 90 percent to 95 percent. But we have to [validate] these antibodies as well, and it will take a few months to [validate] them.

Another major issue is [that] … some homologs to proteins on the Y chromosome [exist] on the X chromosome and other chromosomes. So at the same time we are looking at these proteins and also working on antibodies to these proteins, these homologs. I should also mention that we have a complementary project using transcriptomic approaches, analyzing these genes at the RNA level using real-time PCR and next-generation sequencing databases [as well as] analyzing some of our own samples using next-generation sequencing on an Illumina HiSeq 2000. At the same time we are also using shotgun proteomic analysis for some target tissues like the testes.

So you're doing mass spec-based analysis in addition to the antibody work?

Yes, that is correct. Primarily, though, we are using the antibodies.

What kind of mass spec platforms are you using primarily?

The mass spec that we are using is in collaboration with other groups. We hope that we will be able to use a [Thermo Fisher Scientific] Orbitrap for analyzing our samples. We are collaborating with a group in Australia to analyze the samples. Unfortunately, we don't have appropriate mass spectrometry [instrumentation] for protein analysis in Iran because of the [United Nations] embargo. So the mass spectrometry faculty cannot purchase it. We have interest in mass spectrometry, but our attempt to purchase [an instrument for proteomics work] failed. We approached many companies, but they could not sell these [instruments] to Iran. For antibodies we produce our own, but for mass spectrometry we collaborate with other groups outside the country.

Are you collaborating with any outside groups on antibody development and validation? With Royal Institute of Technology, Stockholm, researcher Matthias Uhlen, for instance, who has been very involved in HUPO's antibody work through his Human Protein Atlas project?

We have all the facilities to validate antibodies including RNAi – we start validating by western blot analysis and immunohistochemistry but then we also use the RNAi approach. But at the end of this we will send our antibodies to Matthias Uhlen's group so that they can also analyze these antibodies.

How long do you anticipate your portion of the C-HPP taking?

The Y chromosome is a small chromosome, so it is easy to work with. Another issue with the Y chromosome is that we actually started working on it [before the launch of the C-HPP.] The [C-HPP] has two phases: phase 1, which is mainly focused on the proteins and their expression in different tissues and the availability of high quality antibodies; and then in the next phase we will be focused on comparing the disease tissues to the healthy ones. But since we already have these samples in Iran, we have already started working on these samples as well.

Another good thing about the Y chromosome project is that more than 50 percent of the Y chromosome proteins so far – based on the available information – are expressed only in the testes, not other tissues. So that makes the research much easier compared to other chromosomes where many of the proteins are expressed in many different tissues.

Another interesting feature of the Y chromosome is that the biology [behind infertility] is [clearly] located on the chromosome. [For example], if you look at the different chromosomes, different genes related to different diseases are located in different chromosomes, so it's hard to point out one disease and one chromosome. But unlike other diseases and chromosomes, it's obvious that [the Y] is the major location for male infertility-related proteins. So to some extent we might be ahead in looking at the diseases related to the Y chromosome.

Do you have any particular clinical goals? Are you looking specifically for biomarkers or are you more interested in just better understanding the underlying biology of these disorders?

So far most of our information about the Y chromosome and male infertility [indicates that] the Y chromosome's connection to male infertility is based on [DNA] microdeletions. That means people could detect microdeletions on the Y chromosome and then correlate those microdeletions to male infertility. But it has been a little bit difficult for researchers to figure out the correlation between some of the proteins [linked to] these mutations and their function. So one of the objectives with the C-HPP project and the Y chromosome project is to [identify] which proteins are directly related to male infertility, and, of course, by finding these proteins it [makes it] much easier to find good biomarkers for male infertility. So [currently] our information about the relation of the [Y chromosome] proteins and [male infertility] is minimal, and we have to maximize this information.

How large is the Y chromosome project? How many labs across Iran are involved?

At the beginning we had three departments in the Royan Institute involved in this project. And now people from different institutions [have gotten involved]. Tehran University, [for instance], just joined the project to do protein structural analysis. And I'm sure that little by little more groups will join the project, probably with their own funding.

Generally speaking, how widely used is proteomics in Iran? Are there any particular areas of focus for proteomics research in the country?

There are several different research institutes and universities involved in this type of proteomics research, and, in fact, it is expanding day by day. I would say that cancer proteomics and also the Y chromosome project and plant proteomics are the major proteomics projects in Iran.

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