By turning skin cells into brain neurons, researchers at the Icahn School of Medicine at Mount Sinai have identified that certain tiny molecules aiding in gene expression, known as microRNAs (miRNAs), are under-expressed in the brains of the 14 schizophrenia patients they studied. Their findings, published online today in the journal Cell Reports, show that one of these molecules, a miRNA known as miR-9, is a risk factor that controls the activity of hundreds of genes.
The researchers, led by Kristen Brennand, PhD, Assistant Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai and Gang Fang, PhD, Assistant Professor in the Department of Genetics and Genomic Sciences, Icahn School of Medicine, found that miR-9 was significantly under-expressed in cells from four schizophrenic patients, compared to six control participants. The findings were replicated in a larger sample, from the National Institutes of Health, of ten childhood-onset schizophrenic patients and ten controls.
“Schizophrenia is a very complex disorder that is believed to be strongly genetically influenced — there are probably more than 1,000 genes contributing to its development, some or many of which will affect individual patients,” says Kristen Brennand, PhD, Assistant Professor of Psychiatry, Icahn School of Medicine at Mount Sinai, and one of the study’s lead authors. “The better we are able to fill in the pieces to this very difficult puzzle, the more we can think about treatment, and, better yet, prevention.”
The genes controlled by miR-9 appear to play a role in the fetal development of neurons, and in where these neurons eventually settle in the brain. If these genes are not as active as they should be, the brain will likely be miswired, the authors suggest. miR-9 is only the second such powerful miRNA linked to the devastating psychiatric disorder, but researchers believe others may be involved.
Dr. Brennand also says that based on their findings, as well as those of other researchers in the field, many genes recently found to be linked to schizophrenia tend to be genes that are expressed during fetal development–even though schizophrenia usually becomes symptomatic in adulthood. “The idea that children are born with schizophrenia should take the pressure off of parents,” she says. “This is a heritable disease that runs in families, and it’s no one’s fault that someone was born with this genetic risk.”
Because the slow progress in decoding schizophrenia comes from the lack of live brain tissue to study, the research team combined expertise in stem cell biology, neurobiology, genomics, and systems biology to pioneer a new approach. They obtained skin samples from patients, reprogrammed them into induced pluripotent stem cells, and then differentiated these cells into precise subtypes of human neurons.
“This has allowed us to begin to ask how and why neurons derived from schizophrenia patients differ from those derived from people who are unaffected by the disorder,” Dr. Brennand says. “The goal of our research is to not just understand the genetic mechanisms contributing to schizophrenia, but ultimately to develop a screening platform that we can use to identify new therapeutics for the treatment of this debilitating disorder.”
The team faced some challenges at the beginning of the project. “miR-9 was not the only miRNA that is differentially expressed in cells from schizophrenia patients compared to control participants,” said Gang Fang PhD, an Assistant Professor in the Department of Genetics and Genomic Sciences and the other lead author of the study. “In fact, tens of miRNAs reached statistical significance and we wanted to identify a smaller number of key players.
We took a systems biology approach, where we integrated miRNA expression, gene expression, global gene regulatory networks, and proteomic data”.
“This approach found evidence suggesting miR-9 has the most significant change of regulatory activity in addition to the expression change of itself,” added Dr. Fang. “We hope this general approach will also help the discovery of additional genetic regulators of schizophrenia and other diseases.”
D. Brennand and Dr. Fang highlight that their team’s findings validate results of an earlier study published March 9 in JAMA Psychiatry, in which a genetic screen, taken from the blood of 35,000 schizophrenia patients, found either low expression or mutations in the hundreds of genes that miR-9 controls.
Additional collaborators include Aaron Topol, Shijia Zhu, Brigham J. Hartley, Ngoc Tran, Chelsea Ann Rittenhouse, Douglas M. Ruderfer, Jessica Johnson, Ben Readhead, Yoav Hadas, Ying-Chih Wang, Hardik Shah, Joel T. Dudley, and Pamela Sklar, from the Icahn School of Medicine at Mount Sinai; Jane English and David Cotter from the Royal College of Surgeons in Ireland; Mads E. Hauberg and Manuel Mattheisen from Aarhus University, Denmark; Anthony Simone and Fred H. Gage from the Salk Institute for Biological Studies; Gerard Cagney from University College, Ireland; Peter A. Gochman and Judith Rapoport from the National Institutes of Health.
Funding: The study was supported by the Brain and Behavior Research Foundation, the New York Stem Cell Foundation and NIH grants R01 MH101454, R01 MH106056, R01 MH097276 and R01 GM114472.
Source: Sasha Walek – Mount Sinai Hospital
Image Source: The image is in the public domain.
Original Research: Full open access research for “Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells” by Aaron Topol, Shijia Zhu, Brigham J. Hartley, Jane English, Mads E. Hauberg, Ngoc Tran, Chelsea Ann Rittenhouse, Anthony Simone, Douglas M. Ruderfer, Jessica Johnson, Ben Readhead, Yoav Hadas, Peter A. Gochman, Ying-Chih Wang, Hardik Shah, Gerard Cagney, Judith Rapoport, Fred H. Gage, Joel T. Dudley, Pamela Sklar, Manuel Mattheisen, David Cotter, Gang Fang, and Kristen J. Brennand in Cell Reports. Published online April 21 2016 doi:10.1016/j.celrep.2016.03.090
Abstract
Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells
Highlights
•miR-9 is highly expressed in NPCs and downregulated in a subset of SZ NPCs
•miR-9 expression level is strongly correlated with miR-9 regulatory activity
•Manipulation of miR-9 impacts neural migration
•miR-9 effects seem to be mediated by small changes in indirect miR-9 targets
Summary
Converging evidence indicates that microRNAs (miRNAs) may contribute to disease risk for schizophrenia (SZ). We show that microRNA-9 (miR-9) is abundantly expressed in control neural progenitor cells (NPCs) but also significantly downregulated in a subset of SZ NPCs. We observed a strong correlation between miR-9 expression and miR-9 regulatory activity in NPCs as well as between miR-9 levels/activity, neural migration, and diagnosis. Overexpression of miR-9 was sufficient to ameliorate a previously reported neural migration deficit in SZ NPCs, whereas knockdown partially phenocopied aberrant migration in control NPCs. Unexpectedly, proteomic- and RNA sequencing (RNA-seq)-based analysis revealed that these effects were mediated primarily by small changes in expression of indirect miR-9 targets rather than large changes in direct miR-9 targets; these indirect targets are enriched for migration-associated genes. Together, these data indicate that aberrant levels and activity of miR-9 may be one of the many factors that contribute to SZ risk, at least in a subset of patients.
“Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells” by Aaron Topol, Shijia Zhu, Brigham J. Hartley, Jane English, Mads E. Hauberg, Ngoc Tran, Chelsea Ann Rittenhouse, Anthony Simone, Douglas M. Ruderfer, Jessica Johnson, Ben Readhead, Yoav Hadas, Peter A. Gochman, Ying-Chih Wang, Hardik Shah, Gerard Cagney, Judith Rapoport, Fred H. Gage, Joel T. Dudley, Pamela Sklar, Manuel Mattheisen, David Cotter, Gang Fang, and Kristen J. Brennand in Cell Reports. Published online April 21 2016 doi:10.1016/j.celrep.2016.03.090
