Epigenetic and functional changes in differentiation and proliferation induced by BORIS expression

• Applicant: Professor Dr. Rainer Renkawitz
• Subject Area: General Genetics and Functional Genome Biology
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 210694066

• Final Report Year: 2016

Final Report Abstract

The ubiquitous and highly conserved factor CTCF is known to mediate the threedimensional organisation and interaction of the genome. In contrast, the cellular role of the paralogous factor CTCFL remained to be solved. CTCFL is specifically expressed in spermatogenesis and aberrantly activated in several cancers. CTCF and CTCFL possess an almost identical DNA binding domain consisting of 11 zinc fingers. The goal of this project was to understand the mechanisms of epigenetic and functional changes induced by CTCFL expression. Three functional aspects have been addressed and could be solved: 1. Expression of CTCFL in mouse ES, NIH3T3 and P19 cells results in deregulation of target genes in a cell type specific manner (results 1 & 4). Loss of CTCFL expression in testis of the mouse causes testicular atrophy and subfertility. 2. A strong overlap between CTCFL binding sites and CTCFL induced genes has been found. 3. Both, the natural binding sites in testis as well as sites bound upon induced CTCFL expression, are enriched for active chromatin marks. In contrast to CTCF, CTCFL is unable to actively “open” chromatin, thus “openness” is a prerequisite for CTCFL binding. Binding site specificity is additionally mediated by a sequence preference.

Publications

• (2012). The male germ cell gene regulator CTCFL is functionally different from CTCF and binds CTCF-like consensus sites in a nucleosome composition-dependent manner. Epigenetics & Chromatin 5(1): 8
  Sleutels, F., W. Soochit, M. Bartkuhn, H. Heath, S. Dienstbach, P. Bergmaier, V. Franke, M. Rosa-Garrido, S. van de Nobelen, L. Caesar, M. van der Reijden, J. C. Bryne, W. van Ijcken, J. A. Grootegoed, M. D. Delgado, B. Lenhard, R. Renkawitz, F. Grosveld and N. Galjart
  
• (2012) CTCF: Insights into insulator function during development. Development 139, 1045-1057
  Herold, M., Bartkuhn, M. and Renkawitz, R.
  
• (2014). CTCF Induces Histone Variant Incorporation, Erases the H3K27me3 Histone Mark and Opens Chromatin. Nucl. Acids Res. 42, 11941-11951
  Weth, O., Paprotka, C., Günther, K., Schulte, A., Baierl, M., Leers, J., Galjart, N. and Renkawitz, R.
  
• (2016). Insulators and domains of gene expression. Curr Opin Genet Dev 37, 17-26
  Ali, T., Renkawitz, R. and Bartkuhn, M.