The primary global aim of the ACE Systems Biomedicine, with 23 leading junior and senior investigators from 13 departments and connecting to 5 facilities, is to understand the mechanistic basis of transcriptional regulation and genome dynamics in cell determination, differentiation, maturation and selected aspects of cellular function in health and disease.
This new research community will carry out fundamental and translational research, use frontline technologies in genomics, proteomics, imaging and genome editing, and proposes 26 collaborative projects, half of these involving new team combinations.
Many senior investigators in this AC have been at the forefront of integrating cellular and molecular techniques into mammalian development, and some have pioneered certain aspects of developmental biology, bringing it together with molecular biology, cell biology, imaging, biochemistry, systems biology and modelling (our fundamental pillar). Collectively, the team leaders of this AC stand for >103,000 citations at present.
Moreover, their research concerned often the origins of human birth defects, and the identification and characterization of stem/progenitor cells in the emerging context of regenerative medicine (including effectively replacing dying cells, yet tumors do not form) as well as of tumorigenesis and tumor invasion/metastasis (our translational pillar, with some outreach to clinical work).
This AC now groups new senior and junior teams that are highly collaborative and integrate their work maximally as a new, strongly synergistic research community. Most groups focus each on a number of individual genes/proteins with an eye for incorporating these in regulatory networks acting in mediation and intrinsic interpretation of cell and tissue interactions. They will continue to engage in very strong multi-team collaborations with many (inter)national top institutes, as can be deduced from their respective co-publications, including over the last 5 years.
This AC educates at Ba, MSc and PhD levels. Each leading investigator supervises (under)graduate students, participates in lecturing, and heavily invests in Ba-MSc education also via lab work supervision, including in Medicine, Molecular Medicine and (new courses in) Nanobiology.
This investment will not change: it is important that students are trained by active, internationally recognized scientists; furthermore, from these students the very best PhD students can be selected for EMC or elsewhere, thus improving EMC's prestige. The aforementioned high-quality education programs as such will continue to exist in the emerging landscape with ACs at EMC, and our AC will support this mission. A major PhD training task awaits our AC. Many of its members are active in doctoral programs. Some teams via funding from FP6/7 consortia (which have training components) have created new jobs and training for young researchers at EMC. Our AC will request funding for PhD students in H2020 and MCS-ITNs. Based on publication quality, obtained funding, recognition in terms of rewards (prizes and fellowships), and the number but above all the quality of trained PhD students (50% from abroad) some of whom are successfully setting-up their own groups, our AC is amongst the top of Dutch biosciences.
Societal Relevance to Research, Education and Patient Care
We ask the most exciting question of biology, which is "How does the fertilized egg develop into an adult organism, where the inherited genome is "read" such that cells differentiate into a specific cell type like neurons, red blood and immune cells, and how organize different cells as embryonic tissues/organs, while small numbers of adult cells maintain stem/progenitor cell status?
We mainly study the function(s) of transcription factor (TF) complexes in the context of interactions and genome structure increasingly in live and/or single cells, crucial next steps to set, and how extrinsic control of cell differentiation/function is interpreted intracellularly as deep as concerted actions of TFs, genome-wide, at target gene/enhancer combinations they control. This transcriptional control is critical for regulating cell proliferation versus arrest, (pluri)potency-differentiation, survival-apoptosis, migration and cell-cell (de)adhesion, each closely linked to pathology. This is why we investigate how deregulation of TF actions can initiate cancer and its progression (particularly leukemia).
Key to the success of this strong and internationally recognized research at EMC will remain the use of novel mass-spectrometry methods, genomics in broadest definition, other genome and protein interaction technologies and imaging, from (sub)cellular down to single-molecule level, backed up by substantial extra efforts in computational biology. The latter includes bio-informatics for omics projects and (live) imaging and quantification, and also encompass challenging mathematical biology-type activities integrating signal transduction and (transcription) regulation into models. EMC needs to empower such new expertise and connect it to frontline research: this AC is in prime position to do so.
Viability of Research, Education and Patient Care
This AC builds on knowledge of molecular studies addressing cell (de)differentiation, studying in particular its transcriptional control, in both healthy and diseased tissue/organs, making this AC an international top player with multiple of its investigators being recognized as key opinion leaders in their field(s).
The complementary expertise needed in this AC is provided by a healthy mixture of senior, established with junior, emerging teams, ensuring the continuity of this AC and the leading position of EMC. The older teams have besides their excellent publication output (in citations, impact factor, h-index) a proven track record of delivering top talents, with many (±50%) coming from abroad and taking-up after their PhD or post-doc with us positions at prestigious institutes and further evolving to independent scientist. Taken together, rejuvenation and internationalization, promotion of mobility, investment in talent and support of career development will be high on our agenda.
Many PhD students (and supervisors) of this AC are embedded in the research school Medical Genetics Center (MGC), a longstanding and very successful EMC-LUMC collaboration, creating awareness of and putting emphasis on multi-disciplinary research and specific technologies, but also widening training in science communication, research integrity and fields like bio-informatics, next-generation sequencing, statistics etc.
Key and relevant publications of the last five years
- Leemans C, van der Zwalm MCH, Brueckner L, Comoglio F, van Schaik T, Pagie L, van Arensbergen J, van Steensel B. Promoter-Intrinsic and Local Chromatin Features Determine Gene Repression in LADs. Cell. 2019 May 2;177(4):852-864.
- Tresini M, Warmerdam DO, Kolovos P, Snijder L, Vrouwe MG, Demmers JA, van IJcken WF, Grosveld FG, Medema RH, Hoeijmakers JH, Mullenders LH, Vermeulen W, Marteijn JA. The core spliceosome as target and effector of non-canonical ATM signalling. Nature. 2015 Jul 2;523(7558):53-8.
- Stryjewska A, Dries R, Pieters T, Verstappen G, Conidi A, Coddens K, Francis A, Umans L, van IJcken WF, Berx G, van Grunsven LA, Grosveld FG, Goossens S, Haigh JJ, Huylebroeck D. Zeb2 Regulates Cell Fate at the Exit from Epiblast State in Mouse Embryonic Stem Cells. Stem Cells. 2017 Mar;35(3):611-625.
- Quevedo M, Meert L, Dekker MR, Dekkers DHW, Brandsma JH, van den Berg DLC, Ozgür Z, van IJcken WFJ, Demmers J, Fornerod M, Poot RA. Mediator complex interaction partners organize the transcriptional network that defines neural stem cells. Nat Commun. 2019 Jun 17;10(1):2669.
- Tüysüz N, van Bloois L, van den Brink S, Begthel H, Verstegen MM, Cruz LJ, Hui L, van der Laan LJ, de Jonge J, Vries R, Braakman E, Mastrobattista E, Cornelissen JJ, Clevers H, Ten Berge D. Lipid-mediated Wnt protein stabilization enables serum-free culture of human organ stem cells. Nat Commun. 2017 Mar 6;8:14578.
- Magini P, Smits DJ, Vandervore L, Schot R, Columbaro M, Kasteleijn E, van der Ent M, Palombo F, Lequin MH, Dremmen M, de Wit MCY, Severino M, Divizia MT, Striano P, Ordonez-Herrera N, Alhashem A, Al Fares A, Al Ghamdi M, Rolfs A, Bauer P, Demmers J, Verheijen FW, Wilke M, van Slegtenhorst M, van der Spek PJ, Seri M, Jansen AC, Stottmann RW, Hufnagel RB, Hopkin RJ, Aljeaid D, Wiszniewski W, Gawlinski P, Laure-Kamionowska M, Alkuraya FS, Akleh H, Stanley V, Musaev D, Gleeson JG, Zaki MS, Brunetti-Pierri N, Cappuccio G, Davidov B, Basel-Salmon L, Bazak L, Shahar NR, Bertoli-Avella A, Mirzaa GM, Dobyns WB, Pippucci T, Fornerod M, Mancini GMS. Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis. Am J Hum Genet. 2019 Oct 3;105(4):689-705.
PhD theses of the last five years
- Nesrin Tüysüz (ten Berge), 2015. Effects of Wnt signaling proteins on maintenance and expansion of adult stem cells.
- Ileana Cantù (Philipsen), 2015. KLF1 in erythroid differentiation.
- Erik Engelen (Poot), 2014. Trancription factor networks in embryonic and neural stem cells.
- Arjan Theil (Vermeulen), 2014. Functional analysis of TTDA: from human to mouse.
- Ralph Stadhouders (Grosveld), 2014. Transcription factors, chromatin loops and blood cells
- Joshua Kapere Ochieng (Rottier), 2014. Sox2 in lung airway epithelial differentiation.
- Widia Soochit (Galjart), 2013. Functional analysis of CTCF and CTCFL.
- Jessica Zuin (Wendt), 2013. Keep in touch! – The role of cohesin and CTCF in organizing the human genome.
- Roel Klein Wolterink (Hendriks), 2013. Stage-dependent function of GATA3 in lymphocyte lineage determination and type-2 immunity.
- Olaf Voets (Verrijzer), 2013, Gene expression control by chromatin binding factors.
Non-scientific publications related to the ACE
- D.L.C. Berg
- C. Cheng
- H.R. Delwel
- M.W.J. Fornerod
- N.J. Galjart
- F.G. Grosveld
- J. Haren
- A.B. Houtsmuller
- D.F.E. Huylebroeck
- G. Jansen
- J.A.F. Marteijn
- J.P.P. Meijerink
- E. Mulugeta
- J.N.J. Philipsen
- R.J. Rottier
- A. Ruiz Saenz
- I.V. Smal
- R. Stadhouders
- D. ten Berge
- H.J.G. van de Werken
- T.J. van Ham
- B. van Steensel
- G.M.S. Verheijen-Mancini
- C.P. Verrijzer
- K.S. Wendt