Prof. Dr. Batu ERMAN
Molecular Biology and Genetics
Kuzey Park, 319
34342 Bebek - Istanbul
+90 (212) 359 6881
|• Batu Erman's personal webpage
• Batu Erman's full resume
We are focused on cells of the immune system. We would like to understand the mechanistic details of how these cells survive, signal and function. We study receptors on the membranes of these cells as well as transcription factors in their nuclei. Our current research projects aim to a) model genetically inherited rare diseases by CRISPR/Cas9 genome editing b) nanobody screening to target signaling pathways in lymphocytes and c) identify rules of dimerization of human transcription factors. Students working on these projects will be exposed to basic and applied scientific research in immunology and molecular biology.
Modeling genetically inherited rare diseases
Recessively inherited rare diseases that affect the immune system are endemic in Turkey because of consanguineous marriage. We first novel mutations in patient samples provided by our medical collaborators and we model these diseases by introducing the identified mutations into immune cell lines using genome engineering and finally we study the structure-function relationships of the identified mutant proteins. A current focus is the CD70 surface protein that is critical for cytotoxic T lymphocyte activity. This protein makes a trimer on the cell surface and is signaled by a ligand, CD27 on opposing cells. A mutant we work with disrupts trimerization and thus decreases ligand affinity. A second focus is the LRBA and CTLA proteins that are critical for regulatory T cell function, which when mutated can cause autoimmune disorders. The study of such mutations will lead to novel drugs that target immunodeficiencies.
Development of nanobodies
Nanobodies are single chain antibodies made by camels, alpacas and llamas. Compared to conventional two chained (heavy+light) antibodies, nanobodies are small and can have very high affinities due to their unique structure. Synthetic libraries can be screened to identify nanobodies that bind target proteins. We are using yeast and phage display libraries of nanobodies to screen for binders to cell surface proteins and also to candidate transcription factors. In this system, nanobodies, encoded by selectable plasmids are expressed on the surface of the yeast S. cerevisiae and captured using magnetic beads conjugated to a target antigen. Several rounds of amplification and selection results in the identification of high affinity binders which can be expressed and purified in E. coli and can be converted into high affinity bioreagents. We are also using computational methods to identify surface activatable sites which we mutagenize to render them cell permeable.
Dimerization of transcription factors
For the past ten years, we have been interested in the human transcription factor PATZ1. This protein is not only important for T lymphocyte development but also has tumor suppressor functions and we have identified that it functionally interacts with the tumor suppressor p53. PATZ1 belongs to the BTB-zinc finger family which has 49 members in mammals. These proteins often suppress transcription by recruiting corepressors and histone deacetylases. Recently we solved the crystal structures of the murine and zebrafish PATZ1 BTB domains (PDB ID: 6GUV and 6GUW) and showed that these proteins form homodimers like most of the other crystallized family members. The mechanism of preferential homodimerization over heterodimerization of these family members is an outstanding question. We are testing several hypotheses: a) preferential degradation of heterodimers (a degron hypothesis), b) structural restrictions of dimer interfaces, c) co-translational dimerization. To assess these models, we have set up a matrix of BTB domains fused to fluorescent proteins and are methodically identifying homodimer versus heterodimer formation by fluorescent microscopy in a fluorescent two hybrid assay. We suspect the identification of the rules of dimerization will shed light on transcriptional regulation and developmental decisions controlled by this family of proteins.
Genome editing technologies
Recently we established novel genome editing technologies in our lab. We use Transcription activator like effector nucleases (TALENs) and the CRISPR/Cas9 system to generate genomic mutations in tissue culture cell lines. We have generated numerous tissue culture cell line derivatives to perform structure-function studies. One of our targets is the IL-7R gene locus. We study transcription factor binding sites in the transcriptional enhancers of re-engineered mutant IL-7R loci to identify the function of these gene regulatory regions.
Anti-cancer and anti-inflammatory drugs
Our work on p53 has led us to design and screen small molecule inhibitors which can be used as anti-proliferative agents against cancer. We have targeted the molecular interaction surface between the MDM2 and p53 proteins. We have several candidate molecules that disrupt this interaction and lead to the accumulation of the p53 protein and result in the death of cancer cells. This activity is specific as p53 deficient cancer cells are not affected by these compounds. We have also generated nanobodies that target the MDM2/MDM4-p53 interaction.
A recent focus in the lab is the IL-1R inflammatory signaling pathway. IL-1R is activated by the cytokine IL-1 and IL-1R accessory protein. A third soluble protein, IL-1Ra (antagonist) binds with high affinity to the receptor and is a competitive inhibitor for IL-1 binding. IL-1Ra has previously been developed as a drug (Kineret/Anakinra) for Rheumatoid arthritis and is used as an anti-inflammatory against Familial Mediterranean Fever (FMF), a classified rare disease which is not so rare in Turkey. Anakinra is produced in bacterial systems and in collaboration with Turkish pharmaceutical companies, we have developed biosimilar and bio-better drug candidates.
- Piepoli, S., Shamloo, B., Bircan, A., Adebali,O., Erman. B. Molecular Biology of SARS-CoV-2 (2020) Turkish Journal of Immunology 8(2):73−88 DOI: 10.25002/tji.2020.1293.
- Piepoli, S. Alt, AO. Atilgan,C. Mancini, EJ. and Erman, B. Structural Analysis of the PATZ1 BTB domain homodimer (2020) Acta Crystallographica Section D. Jun 1;76(Pt 6):581-593. DOI: 10.1107/S2059798320005355.
- Bonjoch,L. Mur,P. Arnau-Collell,C. Vargas-Parra,G. Shamloo,B. Franch-Expósito, S. Pineda,M. Capellà,G. Erman,B. Castellví-Bel,S. Approaches To Functionally Validate Candidate Genetic Variants Involved In Colorectal Cancer Predisposition (2019) Molecular Aspects of Medicine Special Issue: New insights on the molecular aspects of colorectal cancer. DOI: 10.1016/j.mam.2019.03.004.
- Deniz E, Erman B. Long noncoding RNA (lincRNA), a new paradigm in gene expression control (2016) Funct Integr Genomics DOI: 10.1007/s10142-016-0524-x.
- Keskin, N., Deniz, E., Eryilmaz, J., Un, M., Ersahin, T., Cetin Atalay, R., Sakaguchi, S., Ellmeier, W. and Erman, B. PATZ1 is a DNA damage responsive alternatively spliced heterodimeric transcription factor that inhibits p53 function (2015) Molecular and Cellular Biology DOI:10.1128/MCB.01475-14.
- Cevik, S.I., Keskin, N., Deniz, E., Belkaya,S., Ozlu, M.I., Tazebay,U.H., Erman, B. CD81 interacts with the T cell receptor to suppress signaling. PLoS ONE, 2012, 7(11): e50396. DOI:10.1371/journal.pone.0050396.
- Ligons,D.L., Tuncer, C., Linowes, B.A., Akcay, I.M., Kurtulus, S., Deniz, E., Atasever Arslan, B., Cevik, S.I., Keller, H.R., Luckey, M.A., Feigenbaum, L., Möröy,T., Ersahin, T., Atalay, R. and Erman, B., Park, J-H. CD8 Lineage-specific Regulation of Interleukin-7 Receptor Expression by the Transcriptional Repressor Gfi1. Journal of Biological Chemistry. 2012 Oct 5;287(41):34386-99 DOI: 10.1074/jbc.M112.378687.