رسالة جامعية
Functional Analysis of DNA Demethylation - During IL4/GM-CSF-driven Differentiation of Human Monocytes
| العنوان: | Functional Analysis of DNA Demethylation - During IL4/GM-CSF-driven Differentiation of Human Monocytes |
|---|---|
| المؤلفون: | Silva Mendes, Ana Karina da |
| سنة النشر: | 2021 |
| المجموعة: | University of Regensburg Publication Server |
| مصطلحات موضوعية: | 570 Biowissenschaften, Biologie, ddc:570 |
| الوصف: | Epigenetic processes, such as DNA (de)methylation and chromatin remodeling are fundamental for hematopoietic cell differentiation and lineage specification. Hence, their dysregulation is associated with many hematological malignancies. In this thesis, the analyses were focused on DNA demethylation processes during monocyte (MO) to immature dendritic cell (iDC) differentiation in the presence of the cytokines IL4 and GM-CSF. Due to the absence of cell proliferation in this system, we were able to investigate TET-mediated active demethylation events occurring in a replication-independent context. In hematopoietic cells, comprising MO and MO-derived cells, the TET2 enzyme is the main hydroxylase catalysing the initial oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and likely the remaining oxidative steps as well. In this thesis, the TET2 gene was transiently knocked-down in MO using a well-established siRNA-mediated approach and its functional consequences during iDC differentiation were assessed. Overall, TET2 depletion was associated with very mild effects on iDC differentiation, transcriptional programs and chromatin remodeling processes. Nevertheless, the data was reproducible among donors and corroborated the importance of TET2-mediated active DNA demethylation processes during MO differentiation. Based on preliminary genome-wide methylation analyses in MO and iDCs, 7610 iDC-specific differentially methylated regions (DMRs) were identified. These regions were characterized by a progressive active DNA demethylation (5hmC enrichment) and an increase in chromatin accessibility. Since we were mostly interested on differentiation-associated processes, the analyses were centered on transcription factors (TFs) enriched across DMRs and strongly induced in iDCs, such as IRF4 and EGR2. Consequently, both TFs were individually and transiently knocked-down in MO and their effects on iDC differentiation and associated epigenetic processes were determined. IRF4 depletion prevented the differentiation ... |
| نوع الوثيقة: | thesis |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://epub.uni-regensburg.de/43812/1/Doctoral%20Thesis%20Karina%20Mendes.pdfTest; Silva Mendes, Ana Karina da (2021) Functional Analysis of DNA Demethylation - During IL4/GM-CSF-driven Differentiation of Human Monocytes. Dissertation, Universität Regensburg. |
| الإتاحة: | https://epub.uni-regensburg.de/43812Test/ https://epub.uni-regensburg.de/43812/1/Doctoral%20Thesis%20Karina%20Mendes.pdfTest |
| حقوق: | cc_by_4 |
| رقم الانضمام: | edsbas.DBC1FF03 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |