Center for Molecular Medicine Cologne

Abstract

During vertebrate embryonic development different cell-types and tissues are progressively formed, acquiring positional identities according to tightly regulated spatiotemporal patterning.

Numerous transcription factors (TF) with repressive activity (i.e. transcriptional repressors) regulate this process by establishing, along with activators and morphogens, spatio-temporally restricted gene expression domains.

However and compared to activators, much less is known regarding the role of transcriptional repressors in embryonic patterning, their gene targets, molecular regulatory mechanisms and the genomic context in which they act during development.

To study the developmental function of transcriptional repressors we are using a multidisciplinary approach that combines genomics, biochemistry and in vitro differentiation models (e.g. mouse and human embryonic stem cells (ESC)) with in vivo studies using model organisms.

Proposed studies will elucidate molecular mechanisms by which repressor proteins regulate cell-type specific gene expression, embryonic patterning and cellular heterogeneity.

This work will expand our knowledge of gene regulation during embryogenesis and will have broad implications for understanding human development and disease.

  • Ishorst N, Henschel L, Thieme F, Drichel D, Sivalingam S, Mehrem SL, Fechtner AC, Fazaal J, Welzenbach J, Heimbach A, Maj C, Borisov O, Hausen J, Raff R, Hoischen A, Dixon M, Rada-Iglesias A, Bartusel M, Rojas-Martinez A, Aldhorae K, Braumann B, Kruse T, Kirschneck C, Spanier G, Reutter H, Nowak S, Golz L, Knapp M, Buness A, Krawitz P, Nothen MM, Nothnagel M, Becker T, Ludwig KU, and Mangold E (2023). Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores. Mol Genet Genomic Med 11, e2109. doi:10.1002/mgg3.2109.
  • Stussel LG, Hollstein R, Laugsch M, Hochfeld LM, Welzenbach J, Schroder J, Thieme F, Ishorst N, Romero RO, Weinhold L, Hess T, Gehlen J, Mostowska A, Heilmann-Heimbach S, Mangold E, Rada-Iglesias A, Knapp M, Schaaf CP, and Ludwig KU (2022). MiRNA-149 as a Candidate for Facial Clefting and Neural Crest Cell Migration. J Dent Res101, 323-330. doi:10.1177/00220345211038203.
  • Vicioso-Mantis M, Fueyo R, Navarro C, Cruz-Molina S, van Ijcken WFJ, Rebollo E, Rada-Iglesias A, and Martinez-Balbas MA (2022). JMJD3 intrinsically disordered region links the 3D-genome structure to TGFbeta-dependent transcription activation. Nat Commun13, 3263. doi:10.1038/s41467-022-30614-y.
  • Bleckwehl T, Crispatzu G, Schaaf K, Respuela P, Bartusel M, Benson L, Clark SJ, Dorighi KM, Barral A, Laugsch M, van IWFJ, Manzanares M, Wysocka J, Reik W, and Rada-Iglesias A (2021). Enhancer-associated H3K4 methylation safeguards in vitro germline competence. Nat Commun12, 5771. doi:10.1038/s41467-021-26065-6.
                                  • Crispatzu G, Rehimi R, Pachano T, Bleckwehl T, Cruz-Molina S, Xiao C, Mahabir E, Bazzi H, and Rada-Iglesias A (2021). The chromatin, topological and regulatory properties of pluripotency-associated poised enhancers are conserved in vivo. Nat Commun12, 4344. doi:10.1038/s41467-021-24641-4.
                                                                                                                                                    • Kargapolova Y, Rehimi R, Kayserili H, Bruhl J, Sofiadis K, Zirkel A, Palikyras S, Mizi A, Li Y, Yigit G, Hoischen A, Frank S, Russ N, Trautwein J, van Bon B, Gilissen C, Laugsch M, Gusmao EG, Josipovic N, Altmuller J, Nurnberg P, Langst G, Kaiser FJ, Watrin E, Brunner H, Rada-Iglesias AKurian L, Wollnik B, Bouazoune K, and Papantonis A (2021). Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology. Nat Commun12, 3014. doi:10.1038/s41467-021-23327-1.
                                                                                                                                                                        • Koester J, Miroshnikova YA, Ghatak S, Chacon-Martinez CA, Morgner J, Li X, Atanassov I, Altmuller J, Birk DE, Koch M, Bloch W, Bartusel M, Niessen CM, Rada-Iglesias A, and Wickstrom SA (2021). Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility. Nat Cell Biol23, 771-781. doi:10.1038/s41556-021-00705-x.
                                                                                                                                                                                                                                                    • Pachano T, Sanchez-Gaya V, Ealo T, Mariner-Fauli M, Bleckwehl T, Asenjo HG, Respuela P, Cruz-Molina S, Munoz-San Martin M, Haro E, van IWFJ, Landeira D, and Rada-Iglesias A (2021). Orphan CpG islands amplify poised enhancer regulatory activity and determine target gene responsiveness. Nat Genet53, 1036-1049. doi:10.1038/s41588-021-00888-x.
                                                                                                                                                                                                                                                                                                                                              • Stussel LG, Hollstein R, Laugsch M, Hochfeld LM, Welzenbach J, Schroder J, Thieme F, Ishorst N, Romero RO, Weinhold L, Hess T, Gehlen J, Mostowska A, Heilmann-Heimbach S, Mangold E, Rada-Iglesias A, Knapp M, Schaaf CP, and Ludwig KU (2021). MiRNA-149 as a Candidate for Facial Clefting and Neural Crest Cell Migration. J Dent Res, 220345211038203. doi:10.1177/00220345211038203.
                                                                                                                                                                                                                                                                                                                                                              • Thues C, Valadas JS, Deaulmerie L, Geens A, Chouhan AK, Duran-Romana R, Schymkowitz J, Rousseau F, Bartusel M, Rehimi R, Rada-Iglesias A, Verstreken P, and Van Esch H (2021). MAPRE2 mutations result in altered human cranial neural crest migration, underlying craniofacial malformations in CSC-KT syndrome. Sci Rep11, 4976. doi:10.1038/s41598-021-83771-3.
                                                                                                                                                                                                                                                                                                                                                              • Welzenbach J, Hammond NL, Nikolić M, Thieme F, Ishorst N, Leslie EJ, Weinberg SM, Beaty TH, Marazita ML, Mangold E, Knapp M, Cotney J, Rada-Iglesias A, Dixon MJ, Ludwig KU. Integrative approaches generate insights into the architecture of non-syndromic cleft lip with or without cleft palate. HGG Adv. 2021 Jun 8;2(3):100038. doi: 10.1016/j.xhgg.2021.100038. eCollection 2021 Jul 8. PMID: 35047836
                                                                                                                                                                                                                                                                                                                                                              • Bastida MF, Perez-Gomez R, Trofka A, Zhu J, Rada-Iglesias A, Sheth R, Stadler HS, Mackem S, and Ros MA (2020). The formation of the thumb requires direct modulation of Gli3 transcription by Hoxa13. Proc Natl Acad Sci U S A 117, 1090-6.
                                                                                                                                                                                                                                                                                                                                                              • Boles NC, Fernandes M, Swigut T, Srinivasan R, Schiff L, Rada-Iglesias A, Wang Q, Saini JS, Kiehl T, Stern JH, Wysocka J, Blenkinsop TA, and Temple S (2020). Epigenomic and Transcriptomic Changes During Human RPE EMT in a Stem Cell Model of Epiretinal Membrane Pathogenesis and Prevention by Nicotinamide. Stem Cell Reports 14, 631-47.
                                                                                                                                                                                                                                                                                                                                                              • Fatima A, Irmak D, Noormohammadi A, Rinschen MM, Das A, Leidecker O, Schindler C, Sanchez-Gaya V, Wagle P, Pokrzywa W, Hoppe T, Rada-Iglesias A, and Vilchez D (2020). The ubiquitin-conjugating enzyme UBE2K determines neurogenic potential through histone H3 in human embryonic stem cells. Commun Biol 3, 262.
                                                                                                                                                                                                                                                                                                                                                              • Sanchez-Gaya V, Mariner-Fauli M, and Rada-Iglesias A (2020). Rare or Overlooked? Structural Disruption of Regulatory Domains in Human Neurocristopathies. Frontiers in genetics 11, 688.
                                                                                                                                                                                                                                                                                                                                                              Prof. Dr. Alvaro Rada-Iglesias CMMC Cologne
                                                                                                                                                                                                                                                                                                                                                              Prof. Dr. Alvaro Rada-Iglesias

                                                                                                                                                                                                                                                                                                                                                              Institute ofInstitute of Biomedicine and Biotechnology - University of Cantabria, ESomedicine and Biotechnology of Cantabria

                                                                                                                                                                                                                                                                                                                                                              CMMC - assoc. RG 18 (former CMMC JRG Leader)

                                                                                                                                                                                                                                                                                                                                                              +49 221 478 96988

                                                                                                                                                                                                                                                                                                                                                              +49 221 478 97902

                                                                                                                                                                                                                                                                                                                                                              Institute ofInstitute of Biomedicine and Biotechnology - University of Cantabria, ESomedicine and Biotechnology of Cantabria

                                                                                                                                                                                                                                                                                                                                                              present address: Calle Albert Einstein 22

                                                                                                                                                                                                                                                                                                                                                              39011 Santander

                                                                                                                                                                                                                                                                                                                                                              http://zmmk-ari.uni-koeln.de/Rada-Iglesias_lab___Developmental_genomics/Home.html

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