DiNGS

Dissecting the genetic causes of schizophrenia

Schizophrenia (SCZ) is one of the most devastating diseases of the central nervous system and affects about 1% of the population. Despite these enormous effects, little is known about the molecular mechanisms of disease development. Since SCZ has a high heritability and thousands of genetic variants (SNPs) are statistically linked to SCZ, genetics offers promising ways to decipher the disease mechanisms. The aim of this project is to translate genetic associations into a better understanding of molecular disease mechanisms. The hypothesis is that the SCZ phenotype is due to the interplay of many SNPs that interfere with the function of numerous gene regulatory elements (GREs) which are active in neural cell populations.

The work plan includes
1.) The prediction of the functional contribution of SCZ-associated SNPs by combining epigenomic datasets with integrative computational analysis of gene regulatory networks.

2.) The experimental testing of the molecular function of SCZ associated SNPs in neural cell types. For this purpose, a human, pluripotent stem cell differentiation system is utilized to generate various neural cell populations and developmental stages. Epigenomic profiling technology combined with highly parallel reporter assays and CRISPR-based genome engineering will then allow the identification of molecularly functional SNPs in GRE, as well as their molecular effect on individual neural cell types.

3.) The characterization of the physiological effects of combinations of SCZ-associated SNPs. To implement this goal, induced pluripotent stem cells of schizophrenia patients are differentiated into neural cell types in vitro and their physiological properties are compared with normal controls.

 

 

Publications

Ahmad, R., Sportelli, V., Ziller, M., Spengler, D. and Hoffmann, A. (2018). "Tracing Early Neurodevelopment in Schizophrenia with Induced Pluripotent Stem Cells." Cells 7(9). www.ncbi.nlm.nih.gov/pubmed/30227641.

Donaghey, J., Thakurela, S., Charlton, J., Chen, J. S., Smith, Z. D., Gu, H., Pop, R., Clement, K., Stamenova, E. K., Karnik, R., Kelley, D. R., Gifford, C. A., Cacchiarelli, D., Rinn, J. L., Gnirke, A., Ziller, M. J. and Meissner, A. (2018). "Genetic determinants and epigenetic effects of pioneer-factor occupancy." Nature Genetics 50(2): 250-258. www.ncbi.nlm.nih.gov/pubmed/29358654.

Genga, R. M. J., Kernfeld, E. M., Parsi, K. M., Parsons, T. J., Ziller, M. J. and Maehr, R. (2019). "Single-Cell RNA-Sequencing-Based CRISPRi Screening Resolves Molecular Drivers of Early Human Endoderm Development." Cell Rep 27(3): 708-718 e710. www.ncbi.nlm.nih.gov/pubmed/30995470.

Giulitti, S., Pellegrini, M., Zorzan, I., Martini, P., Gagliano, O., Mutarelli, M., Ziller, M. J., Cacchiarelli, D., Romualdi, C., Elvassore, N. and Martello, G. (2018). "Direct generation of human naive induced pluripotent stem cells from somatic cells in microfluidics." Nature Cell Biology. www.ncbi.nlm.nih.gov/pubmed/30598530.

Hoffmann, A., Sportelli, V., Ziller, M. and Spengler, D. (2017). "Epigenomics of Major Depressive Disorders and Schizophrenia: Early Life Decides." International Journal of Molecular Sciences 18(8). www.ncbi.nlm.nih.gov/pubmed/28777307.

Hoffmann, A., Sportelli, V., Ziller, M. and Spengler, D. (2018). "From the Psychiatrist's Couch to Induced Pluripotent Stem Cells: Bipolar Disease in a Dish." International Journal of Molecular Sciences 19(3). www.ncbi.nlm.nih.gov/pubmed/29517996.

Hoffmann, A., Ziller, M. and Spengler, D. (2016). "The Future is The Past: Methylation QTLs in Schizophrenia." Genes 7(12). www.ncbi.nlm.nih.gov/pubmed/27886132.

Hoffmann, A., Ziller, M. and Spengler, D. (2018). "Childhood-Onset Schizophrenia: Insights from Induced Pluripotent Stem Cells." Int J Mol Sci 19(12). www.ncbi.nlm.nih.gov/pubmed/30513688.

Hoffmann, A., Ziller, M. and Spengler, D. (2019). "Progress in iPSC-Based Modeling of Psychiatric Disorders." Int J Mol Sci 20(19). www.ncbi.nlm.nih.gov/pubmed/31581684.

Sheng, C., Jungverdorben, J., Wiethoff, H., Lin, Q., Flitsch, L. J., Eckert, D., Hebisch, M., Fischer, J., Kesavan, J., Weykopf, B., Schneider, L., Holtkamp, D., Beck, H., Till, A., Wüllner, U., Ziller, M. J., Wagner, W., Peitz, M. and Brüstle, O. (2018). "A stably self-renewing adult blood-derived induced neural stem cell exhibiting patternability and epigenetic rejuvenation." Nature Communications 9(1): 4047. www.ncbi.nlm.nih.gov/pubmed/30279449.

Ziller, M. J., Ortega, J. A., Quinlan, K. A., Santos, D. P., Gu, H., Martin, E. J., Galonska, C., Pop, R., Maidl, S., Di Pardo, A., Huang, M., Meltzer, H. Y., Gnirke, A., Heckman, C. J., Meissner, A. and Kiskinis, E. (2018). "Dissecting the Functional Consequences of De Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology." Cell Stem Cell 22(4): 559-574.e559. www.ncbi.nlm.nih.gov/pubmed/29551301.