Hermona Soreq, Ph.D., Professor of Molecular Neuroscience, The Hebrew University of Jerusalem discusses how MicroRNA guardians prevent psychiatric disease by controlling brain-expressed non-coding ‘pseudogenes’…
Psychiatric diseases such as schizophrenia or manic-depressive disorder present an increasingly heavy burden on patients, caretakers and society. These diseases may reflect combined inherited and personal experience-related causes, and currently used psychiatric drugs are confounded by highly variable therapeutic impact. Much effort is being invested these days in identifying those genomic and experience-related elements that differ in patients with psychiatric diseases, with the hope for discovery of brain routes affected by these diseases and for developing new and better therapeutic avenues. The timing is right, because we have only recently realised that much of the human genome, and especially those parts that do not produce proteins and were until not too long ago called ‘junk DNA’ is actually very important. Our advanced ERC project is focused on the role in the human brain of those thousands of tiny genes called microRNAs which constitute part of that infamous ‘junk DNA’. In the brain, microRNAs are known to guard and balance between complete groups of protein-producing genes, keeping brain processes running and preventing functional impairments such as those occurring in psychiatric diseases. To our surprise, we have recently learned that in human brain neurons, microRNAs also guard another group belonging to the category of ‘junk DNA’. Those genes are called ‘pseudogenes’, because they do not produce any protein. They emerged during evolution by duplication of protein-coding ‘mother’ genes, accumulated mutations that prevent them from yielding proteins and were largely considered unimportant, a concept which was changed by our study.
MicroRNAs can only recognise a very small part of the pseudogenes. There are over 17,000 pseudogenes in our genome, but only 123 of them carry recognition signals for some of the 4,000 microRNAs that are expressed in our brain. This makes this group of pseudogenes really special. Importantly, the microRNAs that bind these pseudogenes also need to interact with and control protein production by many other genes; so there is competition going on between ‘real’ genes and those 123 pseudogenes on the microRNAs they share. Since pseudogenes do not produce any protein, they are free to compete with all their might, which implies that they may complicate the job of those microRNAs they recognise, such that any error in their function would interfere with the other roles of the ‘real’ genes that are otherwise controlled by those microRNAs. What we discovered is that such interference is unique to the human brain and that it may appear as psychiatric disease.
Psychiatric genetics teaches us that most of the patients with psychiatric diseases do not carry single mutations in any important gene that could by itself cause, for example schizophrenia or manic-depressive disorder. Rather, it is believed that such patients may carry many small changes in their DNA, each of which causes little modifications that make small differences in how the brain functions; and when those changes appear together, their cumulative impact (sometimes called ‘quantitative trait’) may lead to a psychiatric disease through yet incompletely understood mechanisms. The appearance of many such changes in the genome of a patient may hence indicate a somewhat larger risk of inherited disease for that patient. Therefore, the genomic sites where such changes occur are followed carefully by international groups of researchers, and finding the same changes in large groups of patients may raise alarm signals. For the investigator, finding these flags near important genes may also suggest that those genes that are located nearby to the genomic change fail to do their regular job. This may further hint at what went wrong in the brain of a patient, and yet more importantly- which personalised treatment may best fit the needs of that patient.
Pseudogene-adjacent genomic ‘flags’ were largely ignored in previous studies, because they were considered functionally irrelevant. However, once we discovered that the small group of microRNA-recognising pseudogenes may compete in the human brain with protein-coding genes on their microRNA suppressors, we explored their genomic locations more closely. We found ‘our’ group of pseudogenes to have emerged relatively lately in evolutionary terms by gene duplication. They were also carefully conserved through evolution, meaning that keeping them intact may have an added value; and they compete on the same microRNAs with many genetically unrelated protein-coding genes. Moreover, we discovered that these microRNA-recognising pseudogenes are highly expressed in brain neurons, that they actively participate in brain communication processes, and that their cumulative genomic locations are enriched in frequently occurring DNA changes that are relatively common in schizophrenia, autism and manic-depressive disorder.
While this information supported the new concept that brain pseudogenes which recognise microRNAs may be important, we needed more concrete findings. To this end, we analysed the expression of ‘our’ pseudogenes in embryonic stem cells from schizophrenic and healthy donors, and found that ‘schizophrenic’ stem cells failed to produce their ‘healthy’ levels. Furthermore, when we blocked or increased the expression of such pseudogenes in cultured cells, these interference tests also caused parallel changes in the levels of those ‘real’ gene products that compete with them on microRNAs. Our findings transform the understanding of the so-far neglected small group of microRNA-interacting pseudogenes, opening new avenues for neuro-genetics, diagnostic and therapeutic directions of mental diseases.
Hermona Soreq, Ph.D.
Professor of Molecular Neuroscience
The Edmond and Lily Safra Center for Brain Sciences, Department of Biological Chemistry
The Alexander Silberman Institute of Life Sciences
The Hebrew University of Jerusalem
hermona.soreq@mail.huji.ac.il
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