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Identifier 000428746
Title Chromatin organization at the nuclear periphery : subnuclear localization and expression of microRNA genes in cells of the murine adaptive immune system
Alternative Title Οργάνωση της χρωματίνης στην περιφέρεια του κυτταρικού πυρήνα: υποπυρηνική τοποθέτηση και έκφραση των microRNA γενετικών τόπων στο επίκτητο ανοσοποιητικό σύστημα του ποντικού
Author Salataj, Eralda F.
Thesis advisor Σπηλιανάκης, Χαράλαμπος
Reviewer Γαρίνης, Γεώργιος
Καλαντίδης, Κρίτων
Δελιδάκης, Χρήστος
Νικολάου, Χριστόφορος
Στρούμπουλης, Ιωάννης
Ταλιανίδης, Γιάννης
Abstract The last few years it has become increasingly clear that higher order chromatin organization controls the regulation of genome activity and serves as an additional epigenetic mechanism that modulates cellular functions and gene expression programs in diverse biological processes. Spatial positioning of different gene loci can be directly linked to gene expression while deregulation of the nuclear architecture can be linked to severe diseases. Control of gene expression is of vital importance for all organisms. Allelic interactions and gene repositioning with functional importance are common during the regulation of immune responses. Nowadays more and more studies support the correlation between chromatin organization and gene regulation. Except from the histone modifications and transcription factors non coding RNAs can also control gene expression. MicroRNAs constitute an abundant class of endogenous and highly conserved small non-coding RNAs molecules (ncRNAs) that play an important role in modulating gene expression at the transcriptional and post-transcriptional level. microRNAs have been implicated in quite diverse biological processes including stem cell self-renewal, differentiation, proliferation, apoptosis and the regulation of immune responses in both innate and adaptive immune system. Although there is cumulative information regarding the steady state mature microRNA levels and their respective targets, little is known about the effect of the three-dimensional chromatin architecture on the transcriptional regulation of microRNA gene loci. In this study we sought to investigate the impact of nuclear architecture as an epigenetic mechanism regulating the expression and the subnuclear localization of eight microRNA genes upon transcriptional activation in CD4+ T cells during development and differentiation, in discrete T cell lineages. More specifically, we investigated the role of subnuclear localization of microRNA gene loci as a potential mechanism affecting non-coding genome expression. Apart from highlighting the impact of the nuclear periphery in microRNA gene expression, this study introduces other factors that may modulate the subnuclear positioning or the expression. Our results show that eight microRNA gene loci (miR-181a1b1, miR-181a2b2, miR-181c, miR-142, miR-146a, miR-17-92, miR-155 and miR-let7e) are mainly monoallelically expressed and localized in the cell nuclear periphery irrespective of the gene’s transcriptional status or the cell’s differentiation state. Moreover, our results show that the microRNA Microprocessor complex [comprised by DROSHA and DiGeorge syndrome critical region gene 8 (DGCR8) proteins also localizes in the nuclear periphery of T cells, indicating a functional role in the transcriptional regulation of microRNA genes. We also found that microRNA gene loci were significantly enriched, compared to coding genes, for nuclear pore proteins (NUP) (such as NUP153 and NUP93) implying that nuclear pore proteins may be implicated in tethering microRNA gene loci to the nuclear periphery. The genome organizer protein SATB1 can affect the expression and the localization of microRNA genes in thymocytes but also in CD4+ cells, showing its important role as the main chromatin organizer in T cells. Fianlly, the expression profile and perinuclear localization of microRNA genes are developmentally conserved while their localization outside constitutive lamin associated domains (cLAD) is cross-species conserved in H. sapiens, M. musculus, D. melanogaster and C. elegans. In conclusion all the above data unveil a link between the 3D architecture of chromatin in T cells and its impact on the subnuclear localization and expression of microRNA gene loci. Our results pinpoint the impact of nuclear periphery in microRNA gene expression, shed light on chromatin organization at the nuclear periphery and allow for a better understanding of the T cell genome organization.
Language English
Subject Monoallelic expression
Non coding RNA
Nuclear periphery
Μη κωδικό RNA
Μονοαλληλική έκφραση
Πυρηνική περιφέρεια
Issue date 2019-12-05
Collection   Faculty/Department--Faculty of Sciences and Engineering--Department of Biology--Doctoral theses
  Type of Work--Doctoral theses
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