Nearly all cells of an individual organism contain the same genome. However, each cell type transcribes a different set of genes due to the presence of different sets of cell type-specific transcription factors. Such transcription factors bind to regulatory regions such as promoters and enhancers and regulate their activity in gene transcription. Transcription factors interact with each other and form tissue-specific transcription factor networks. Identification of genome binding and gene regulation by transcription factors will enhance our understanding of how transcription factors specify cell types.  



Chapter 1 serves as a general introduction into eukaryotic transcription regulation and describes the role of enhancers and transcription factors.  Chapters 2 – 4 describe the experimental work  of this thesis.  Chapte

Brandsma, J.H. (Johan)

Nearly all cells of an individual organism contain the same genome. However, each cell type transcribes a different set of genes due to the presence of different sets of cell type-specific transcription factors. Such transcription factors bind to regulatory regions such as promoters and enhancers and regulate their activity in gene transcription. Transcription factors interact with each other and form tissue-specific transcription factor networks. Identification of genome binding and gene regulation by transcription factors will enhance our understanding of how transcription factors specify cell types.  
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\nChapter 1 serves as a general introduction into eukaryotic transcription regulation and describes the role of enhancers and transcription factors.  Chapters 2 \xe2\x80\x93 4 describe the experimental work  of this thesis.  Chapter 2  describes Chromatin Immunoprecipitation followed by Mass Spectrometry (ChIP-MS), a technique used to identify transcription factors and other genome binding proteins that  bind to promoters, enhancers or heterochromatin. Chapter 2 specifically describes the genome-binding pattern of transcription- and pluripotency factor Dppa2, which we identify by ChIP-MS and ChIP-seq to bind to promoters outside the classical pluripotency network. Chapter 3 describes a transcription factor interaction network of over 200 proteins in neural stem cells, which was assembled by the identification of interaction partners of four mental disorder-associated transcription factors. Chapter 4 describes work on the genome-wide localization of Oct4, Sox2 and Nanog in embryonic stem cells and investigates the genome localization of these transcription factors upon depletion of Oct4 or Sox2 from embryonic stem cells. The last chapter, Chapter 5, summarizes the results from Chapter 2-4 and provides additional discussion to these chapters, concerning its implications and future directions

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1. The ChIP-MS method provides a detailed read-out of the transcriptional landscape representative of the investigated cell type (this thesis).2. Dppa2 operates outside the classical pluripotency network (this thesis).3. Interaction partners of transcriptional regulators in neural stem cells such as Tcf4, Sox2, Olig2 and Npas3 are good candidates for mutation screening to identify novel mental disorder genes (this thesis).4. Interaction of transcriptional regulators is a predictor of the similarity in their human phenotypes (this thesis).5. Oct4 recruits Sox2 together with Nanog to binding sites that harbor the composite Sox2-Oct4 DNA binding motif in embryonic stem cells (this thesis).6. The pathogenicity of  human disease-associated deletions can result from ectopic enhancer-promoter interactions, due to the elimination of topological domain boundaries, causing aberrant gene expression. Cell 161:1012-1025 (2015) 7.  “Currently, there does not seem to be a set of rules that cleanly defi nes super-enhancers or emergent properties that set them apart from the traditional enhancer concept”.  Nature Genetics  47(1):8-12 (2015)8. “You can have data without information, but you cannot have information without data” (Daniel Keys Moran)9. “An understanding of the natural world and what’s in it is a source of not only a great curiosity but great fulfi llment, but also in the long run, essential to our future survival.” (David Attenborough)10. “Never memorize something that you can look up” (Albert Einstein)11. “Amit gyűlöltünk, azt most sajnáljuk, és visszasírjuk. Függetlenek vagyunk, de öröm helyett  csak remegni tudunk.”  (Translation: “We now regret the loss and weep for the return of what we once hated. We are now independent, but instead of feeling joy we can only tremble.”). Mihály Babits, 1939, refl ecting on the collapse of the Austrian-Hungarian Monarchy. Translation from ‘The Sleepwalkers’ by Christopher Clark. According to the author of this thesis a historic poetic lesson for people who want to stop and reverse European integration. STELLINGENBEHORENDE BIJ HET PROEFSCHRIFT:Genome Binding and Gene Regulation by Stem Cell Transcription Factorsstellingen.indd   1 1/19/2016   1:18:13 PM

Genome Binding and Gene Regulation by Stem Cell Transcription Factors

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