R. (Ralph) Stadhouders MSc, PhD

Our overarching goal is to decipher the molecular mechanisms that control immune cell phenotypes in both homeostasis and disease to identify targets for therapeutic intervention. We work towards this goal by employing state-of-the-art genomics technology to study gene regulatory mechanisms in mouse and human immune cells. Special emphasis is placed on the identification and characterization of gene regulatory elements and transcription factors critical for lymphocyte dysfunction in asthma, autoimmunity and cancer. Disease-relevant cell populations are obtained from mouse models that mimic human immune disorders and patient material from the clinic or collaborations with nearby hospitals.

Ralph Stadhouders obtained his MSc and PhD degrees at Erasmus University Rotterdam. During this period, he studied gene regulatory mechanisms in developing blood cells at the Department of Cell Biology under the guidance of Dr. Eric Soler and Prof. Frank Grosveld. He then obtained several postdoctoral fellowships to relocate to Barcelona (Spain) and join the laboratory of Prof. Thomas Graf at the Centre for Genomic Regulation (CRG). There he studied how transcription factors rewire the transcriptome and epigenome during the reprogramming of lymphocytes into pluripotent stem cells. In 2017 he returned to the Erasmus MC and initiated his own line of research in collaboration with the Department of Cell Biology (Prof. Danny Huylebroeck & Prof. Frank Grosveld). Operating at the interface between fundamental and translational science, his current research focuses on understanding the molecular switches that cause lymphocyte dysfunction in immunological diseases.

1. Stadhouders R, Filion GJ, Graf T. (2019). Transcription factors and 3D genome conformation in cell-fate decisions. Nature 569, 345-354.
2. Stadhouders R, Vidal E, Serra F, Di Stefano B, Le Dily F, Quilez J, Gomez A, Collombet S, Berenguer C, Cuartero Y, Hecht J, Filion G, Beato M, Marti-Renom MA, Graf T. (2018). Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming. Nature Genetics. 50(2):238-249.
3. Lim AI, Li Y, Lopez-Lastra S, Stadhouders R, Paul F, Casrouge A, Serafini N, Puel A, Bustamante J, Surace L, Masse-Ranson G, David E, Strick-Marchand H, Le Bourhis L, Cocchi R, Topazio D, Graziano P, Muscarella LA, Rogge L, Norel X, Sallenave JM, Allez M, Graf T, Hendriks RW, Casanova JL, Amit I, Yssel H, Di Santo JP (2017). Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Cell. 168(6):1086-1100.
4. Stadhouders R, Li BWS, de Bruijn MJW, Gomez A, Rao TN, Fehling HJ, van IJcken WFJ, Lim AI, Di Santo JP, Graf T, Hendriks RW (2018). Epigenome analysis links gene regulatory elements in group 2 innate lymphocytes to asthma susceptibility. J Allergy Clin Immunol. 142:1793-1807.
5. Brouwer RW, van den Hout MC, van IJcken WF, Soler E#, Stadhouders R#. (2017). Unbiased Interrogation of 3D Genome Topology Using Chromosome Conformation Capture Coupled to High-Throughput Sequencing (4C-Seq). Methods in Molecular Biology. 1507:199-220.

Both CD4+ T helper 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and have been implicated in various immune disorders including allergic asthma. We generated the first epigenome maps of circulating human ILC precursors and ILC2s, revealing novel putative regulators of human ILC biology and supporting a pathogenic role ILC2s in allergic asthma. More recently, we identified a human inflammatory ILC2 population, marked by CD45RO expression, that is increased in the circulation of patients with chronic rhinosinusitis or asthma, correlating with disease severity and resistance to corticosteroid therapy. Based on computational integration of high-resolution genome-wide datasets of nuclear architecture, chromatin structure and gene expression, we demonstrated that human Th2 cells carry a unique chromatin landscape synergistically reprogrammed at both one-dimensional (1D) and 3D levels to accommodate recall responses. Interestingly, resting memory Th2 cells from patients with asthma showed premature activation of primed recall circuits, linking aberrant transcriptional control of recall responses to chronic inflammation. Finally, we recently identified type 2 cytokine producing CD8+ T cells as major effectors in severe asthma and during asthma exacerbation.

FIGURE 1 | Pathophysiology of type-2 asthma

FIGURE 2 | Different genome folding dynamics underlie innate and adaptive immune responses