Sebo Withoff, PhD
Immune system, T-cells, B-cells, miRNA’s, functional genomics, lincRNAs
My main research interest is how an individual’s genetic make-up contributes to immune homeostasis in healthy individuals versus in autoimmune disease susceptibility. Recently, two pivotal observations have been made about the genetics of autimmune disease susceptiblity: (1) a considerable part of the genetic architecture of autoimmune diseases is shared between different autoimmune diseases, and (2) most genetic factors associated with autoimmune diseases (disease-associated single nucleotide polymorphisms (SNPs)) do not seem to alter the amino-acid sequence of protein-encoding genes but instead associate with (a) gene regulatory regions or (b) non-coding RNA genes. Based on this, I am currently focusing on the following questions:
- How does the genetic background affect an individual’s immune cell function in health and (autoimmune) disease?
- How do SNPs in gene regulatory regions affect the expression of genes associated with autoimmune diseases?
- What is the role of non-coding RNAs in autoimmune diseases?
I am focusing on celiac disease as a model system for autoimmune diseases in general. However, my research has implications for other diseases as well, such as multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis. Because of the shared genetics of autimmune diseases, results obtained for celiac disease can have an immediate broader impact. To gain insight into the genetics and the etiology of these autoimmune diseases, we are using sophisticated genomics approaches (genome-wide association studies, pathway analysis) and state-of-the-art wet biology approaches (FACS, next generation sequencing, CRISPR/Cas9 technology) in house.
Current Research Projects
These projects are being performed within the context of Prof. Cisca Wijmenga’s research group. Several other PIs and technicians in the Dept. of Genetics are involved to varying degrees.
- We are using next generation sequencing to identify which genes are deregulated by prioritized disease-associated SNPs. Subsequent pathway analysis approaches are used to predict disease mechanisms. An anchoring point in this research are disease-associated loci (found by genome-wide association studies) and the coding and non-coding genes therein. The results of these prioritization studies are being used for the rational design of in vitro experiments.
- I am investigating whether circulating miRNAs are biomarkers for immune mediated diseases. Currently, I am focusing circulating miRNAs in plasma of celiac disease patients and in plasma or CSF of multiple sclerosis patients.
- We are studying the role of long non-coding RNAs (lncRNAs) in celiac disease and other autoimmune conditions. Using in silico approaches, multiple lincRNA genes have been identified in the celiac disease risk loci. Most of these candidate lincRNAs were initially identified in T cells, a cell type that plays an important role in the pathology of celiac disease and other autoimmune diseases. We are profiling lincRNAs in the immune cells of genotyped individuals and are screening for disease-associated mutations in lincRNAs by deep sequencing. To study the role of candidate lincRNAs in immune cell function, we are designing vectors to modify their expression levels in vitro by overexpression and knock-down approaches.
- Some of the genes prioritized in our pathway analyses appear to play a role in intestinal barrier function. Currently we are using CaCo2 sublines as model systems for this, but we are working towards a system that uses urine-derived iPS cells (from patients and healthy volunteers) that we want to differentiate in vitro towards the epithelial lineage.
- We are applying cutting-edge molecular techniques to study disease-causing genetic variation in specific cell types (single sequencing approaches) and can modify these genetic factors in a particular background using CRISPR/Cas9 technology.
I studied Biology (specialization in Biochemistry) at the University of Groningen and in 1996 I obtained my PhD there (thesis: “The role of DNA Topoisomerase II in drug resistance and sensitivity”). My research interest then shifted more towards immunology. I performed post-doc research in the Netherlands, in the Dept. of Medical Oncology, University Medical Center Groningen (Prof. E.G.E. de Vries & Prof. N.H. Mulder), in the Dept. of Physiological Chemistry, University of Groningen (Prof. J.C. Wilschut), and in the Dept. of Medical Biology (Prof. L.F.M.H. de Leij). Then I worked in the USA as a post-doc in the lab of Dr. Inder Verma (Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA) and as a staff scientist in the lab of Dr. Douglas Green (Department of Immunology, St Jude Children’s Research Hospital, Memphis, TN). I returned to the Netherlands in 2011 where I am now an assistant professor in the Dept. of Genetics, UMCG.
I have published several papers in high impact journals, such as Nature Genetics, Nature, Cell, and Blood (see full list in Google Scholar). Papers most relevant for my ongoing studies are:
Y Li, …, S Withoff, …, MG Netea A Functional Genomics Approach to Understand Variation in Cytokine Production in Humans Cell 167, 1099-1110 (2016) .
I Ricaño-Ponce , …, S Withoff, ..., V Kumar Refined mapping of autoimmune disease associated genetic variants with gene expression suggests an important role for non-coding RNAs J Autoimmun 68, 62-74 (2016).
S Withoff, Y Li, I Jonkers, and C Wijmenga Understanding celiac disease by genomics Trends in Genetics 32, 295-308 (2016).
V Kumar, J Gutierrez-Achury, K Kanduri, R Almeida, B Hrdlickova, ... S Withoff Systematic annotation of celiac disease loci refines pathological pathways and suggests a genetic explanation for increased interferon-gamma levels Human Molecular Genetics 24, 397-409 (2015).
R Almeida, I Ricaño-Ponce, V Kumar, P Deelen, A Szperl, G Trynka, ... S Withoff, C Wijmenga Systematic annotation of celiac disease loci refines pathological pathways and suggests a genetic explanation for increased interferon-gamma levels Human Molecular Genetics 24, 397-409 (2015).
B Hrdlickova, V Kumar, K Kanduri, DV Zhernakova, S Tripathi, ... S Withoff Expression profiles of long non-coding RNAs located in autoimmune disease-associated regions reveal immune cell-type specificity Genome medicine 6, 88 (2014).
B Hrdlickova, RC de Almeida, Z Borek, S Withoff Genetic variation in the non-coding genome: Involvement of micro-RNAs and long non-coding RNAs in disease Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1842, 1910–1922 (2014).
A Zhernakova, S Withoff, C Wijmenga Clinical implications of shared genetics and pathogenesis in autoimmune diseases Nature Reviews Endocrinology 9, 646-659 (2013).
HJ Westra, MJ Peters, ..., S Withoff, ..., L Franke. Systematic identification of trans eQTLs as putative drivers of known disease associations Nature Genetics 45, 1238-1243 (2013).
V Kumar, C Wijmenga and S Withoff. From genome-wide association studies to disease mechanisms: celiac disease as a model for autoimmune diseases. Semin Immunopathol. 1-14 (2012).
DC Spierings, ... S Withoff. Ordered progression of stage-specific miRNA profiles in the mouse B2 B-cell lineage. Blood 117, 5340-5349 (2011).
MA Sanjuan, ... S Withoff and DR Green. Toll-like receptor signaling in macrophages links the autophagy pathway to phagocytosis. Nature 450, 1253-1257 (2007).
If you are a student and you are interested in an internship in my group, please drop me an email. Undoubtedly we will have fresh plans by the time you read this, but links to current projects are:
|Laatst gewijzigd:||08 maart 2017 09:52|