Friday, 2 December 2011

Research:Transcription analysis points to SP1

* Menon R et al. Gender-based blood transcriptomes and interactomes in multiple sclerosis: Involvement of SP1 dependent gene transcription. J. Autoimmunol 2011. Nov [Epub]


In this study we investigated the contribution of gender to global gene expression in peripheral blood mononuclear cells (T cell, B cell, monocyte-white blood cells) from multiple sclerosis (MS) patients and healthy controls. We observed that, in contrast to the conventional approach, gender (male-female)-based case-control comparisons resulted in genelists with significantly reduced heterogeneity (variability) in human populations. In addition, MS was characterized by significant changes both in the quantity and in the quality of the sex-specific genes.

Application of stringent statistics defined gender-based signatures which classified a further sample of MSers with high precision. The global unsupervised cluster analyses for 60 subjects showed that 29/31 female and 27/29 male samples were properly identified. Notably, MS was associated in women and in men with distinct gene signatures, which however shared several molecular functions, biological processes and interactors. Issues regarding epigenetic control of gene expression appeared as the main common theme for disease, with a central role for the functional modules related to histone deacetylase, NF-kappaB and androgen (male sex hormone) receptor signaling. Moreover, computer analyses predicted that the differential expression in MS women and men were depending on the transcription factor SP1.

Gene transcripts were either high (green) or low (red)


Specific targeting of this pathway by the bis-anthracycline WP631 impaired T cell responses in vitro (cell culture) and in vivo(animals), and reduced the incidence and the severity of experimental autoimmune encephalomyelitis, indicating that SP1 dependent gene transcription sustains neuroinflammation. Thus, the gender-based approach with its reduced heterogeneity and the systems biology tools with the identification of the molecular and functional networks successfully uncovered the differences but also the commonalities associated to multiple sclerosis in women and men. In conclusion, we propose gender-based systems biology as a novel tool to gain fundamental information on disease-associated functional processes.

This study indicates that gene specific signatures (identifying clusters of genes that can be linked to some function) can be found in MSers that include the influence of gender. However, rather than this simple being the influence of the genetic code that gives the signature, this signatures is often controlled by factors that modify the reading of the genetic code. The analysis of MSers interesting pointed towards the SP1 transcription factor, which is interesting as it further highlights an immune component in MS. However, that SP1 modulation is important in immune function is not surprising as this is one of the ways that Gilenya works (licensed MS drug). Itt is therefore a bit of a non-brainer to predict that a drug WP31 inhibitor would inhibit T cell responses and inhibit the development of EAE, which is known to be dependent on T cell function.

5 comments:

  1. Gilenya has been, once again, turned down by N.I.C.E. on grounds of not being cost effective. This is despite Novartis Pharmaceuticals UK proposing a discount (Patient Access Scheme) to the price of Gilenya.

    Stuff like this makes me wonder just how bleak the MS scene is. Drugs take ages to materialise, and when they do the Government just shoots it down.

    If, hopefully, Fingolimod shows improvement in PPMS, I bet N.I.C.E. once again rejects it.

    Is there anything we PwMS can do to improve the availability and access to drugs? Who do we cajole, lobby and pressure?

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  3. Is SP1 transcription factor only involved in modulating the immune activity? In which other processes is it also involved? What makes you think that its main contribution to MS is through immunity?

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  4. Fair point.

    Yes of course SP1 does other things.

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  5. This was hard work

    http://www.pbs.org/wgbh/nova/body/epigenetics.html
    http://ghr.nlm.nih.gov/glossary=transcription
    http://ghr.nlm.nih.gov/glossary=transcriptionfactor
    http://www.ncbi.nlm.nih.gov/books/NBK21126/def-item/A10069/

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