TY - JOUR A1 - Schneider, Eberhard A1 - Dittrich, Marcus A1 - Böck, Julia A1 - Nanda, Indrajit A1 - Müller, Tobias A1 - Seidmann, Larissa A1 - Tralau, Tim A1 - Galetzka, Danuta A1 - El Hajj, Nady A1 - Haaf, Thomas T1 - CpG sites with continuously increasing or decreasing methylation from early to late human fetal brain development JF - Gene N2 - Normal human brain development is dependent on highly dynamic epigenetic processes for spatial and temporal gene regulation. Recent work identified wide-spread changes in DNA methylation during fetal brain development. We profiled CpG methylation in frontal cortex of 27 fetuses from gestational weeks 12-42, using Illumina 450K methylation arrays. Sites showing genome-wide significant correlation with gestational age were compared to a publicly available data set from gestational weeks 3-26. Altogether, we identified 2016 matching developmentally regulated differentially methylated positions (m-dDMPs): 1767 m-dDMPs were hypermethylated and 1149 hypomethylated during fetal development. M-dDMPs are underrepresented in CpG islands and gene promoters, and enriched in gene bodies. They appear to cluster in certain chromosome regions. M-dDMPs are significantly enriched in autism-associated genes and CpGs. Our results promote the idea that reduced methylation dynamics during fetal brain development may predispose to autism. In addition, m-dDMPs are enriched in genes with human-specific brain expression patterns and/or histone modifications. Collectively, we defined a subset of dDMPs exhibiting constant methylation changes from early to late pregnancy. The same epigenetic mechanisms involving methylation changes in cis-regulatory regions may have been adopted for human brain evolution and ontogeny. KW - Autism spectrum disorders KW - DNA methylation KW - Genome KW - Autism KW - Frontal cortex KW - Human prefrontal cortex KW - Gene-expression KW - Schizophrenia KW - Patterns KW - Transcription KW - Epigenetics KW - Environment KW - Fetal brain development KW - DNA methylation dynamics KW - Methylome Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186936 VL - 592 IS - 1 ER - TY - THES A1 - Lorenzin, Francesca T1 - Regulation of transcription by MYC - DNA binding and target genes T1 - Transkriptionelle Regulation durch MYC - DNA-Bindung und Zielgene N2 - MYC is a transcription factor, whose expression is elevated or deregulated in many human cancers (up to 70%) and is often associated with aggressive and poorly differentiated tumors. Although MYC is extensively studied, discrepancies have emerged about how this transcription factor works. In primary lymphocytes, MYC promotes transcriptional amplification of virtually all genes with an open promoter, whereas in tumor cells MYC regulates specific sets of genes that have significant prognostic value. Furthermore, the set of target genes that distinguish MYC’s physiological function from the pathological/oncogenic one, whether it exists or not, has not been fully understood yet. In this study, it could be shown that MYC protein levels within a cell and promoter affinity (determined by E-box presence or interaction with other proteins) of target genes toward MYC are important factors that influence MYC activity. At low levels, MYC can amplify a certain transcriptional program, which includes high affinity binding sites, whereas at high levels MYC leads to the specific up- and down regulation of genes with low affinity. Moreover, the promoter affinity characterizes different sets of target genes which can be distinguished in the physiological or oncogenic MYC signatures. MYC-mediated repression requires higher MYC levels than activation and formation of a complex with MIZ1 is necessary for inhibiting expression of a subset of MYC target genes. N2 - MYC ist ein Transkriptionsfaktor, dessen Expression in vielen humanen Tumoren (bis zu 70 %) erhöht oder dereguliert ist. Die Tumore, in denen viel MYC hergestellt wird, zeichnen sich durch einen geringen Differenzierungsgrad aus und verhalten sich sehr aggressiv. Obwohl das biologische Verhalten des MYC Proteins intensiv untersucht wurde, sind unterschiedliche Modelle, wie dieser Transkriptionsfaktor funktioniert, entwickelt worden. In primären Lymphozyten verstärkt MYC die Expression fast aller Gene mit offener Chromatinstruktur, während MYC in Tumorzellen spezifische Gengruppten reguliert, deren Expression mit der Prognose von Patienten korreliert. Es ist also unklar, ob sich die Zielgene der physiologischen Funktion von Myc von den oncogenen/pathophysiologischen Zielgenen unterscheidet und um welche Gene es sich bei letzteren handelt. In dieser Arbeit konnte gezeigt werden, dass Expressionsniveau von MYC und unterschiedliche Promotoraffinitäten zu MYC (charakterisiert durch den Ebox-Gehalt und Interaktionen zu anderen Proteinen) wichtig für die Aktivität des MYC Proteins sind. So kann Myc bei niedrigen Konzentrationen ein bestimmtes transkriptionelles Programm amplifizieren, das sich aus hochaffinen Promotoren zusammensetzt. Bei hohen Konzentrationen hingegen führt MYC zur transkriptionellen Aktivierung und Repression bestimmter Zielgengruppen, die sich durch niedrige Affinität zu MYC auszeichnen. Somit ist die Promotoraffinität ein Parameter, der physiologische von oncogenen MYC Signaturen trennen kann. Darüberhinaus konnte gezeigt werden, dass MYC-vermittelte Repression höhere MYC Mengen benötigt, als MYC-vermittelte Transaktivierung und die Komplexbildung mit MIZ1 für die Repression einer Gruppe an MYC Zielgenen nötig ist. KW - MYC KW - Transcription Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150766 ER -