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Identifier 000446012
Title Defining the SATB1-dependent 3D chromatin structure in CD4+ cells
Alternative Title Η πρωτεΐνη SATB1 καθορίζει την τρισδιάστατη δομή της χρωματίνης σε CD4+ κύτταρα
Author Zelenka, Tomáš
Thesis advisor Σπηλιανάκης, Χαράλαμπος
Reviewer Γαρίνης, Γεώργιος
Strouboulis, John
Μαυροθαλασσίτης, Γεώργιος
Ταλιανίδης, Γιάννης
Θάνος, Δημήτρης
Δελιδάκης, Χρήστος
Abstract The understanding of mechanisms behind gene expression regulation constitutes a primary objective of modern biology. Human health is largely dependent on the proper function of the immune system. An essential part of it is represented by T lymphocytes which exist in various forms with different functionalities. The enormous flexibility and plasticity of T cell development is determined by a complex interplay of many transcriptional programs and therefore T cells serve as a good model to study transcriptional regulation. In this work we investigated the regulatory processes involved in transcriptional control of developing T cells. We described the 3D regulatory chromatin network and identified its key mediator, a tissuespecific protein SATB1. Our findings unravel the function of SATB1 that controls transcription programs via at least three different mechanisms. The tight regulation of different SATB1 protein isoform levels and their post-translational modifications are imperative for SATB1’s phase transitions associated with transcription and splicing. Cooperation of SATB1 and noncoding RNA Xist is decisive for female T cell-specific transcriptional regulation of X-linked immune-related genes. Their concerted action also represents a novel complementary mechanism contributing to silencing of the immunoglobulin gene loci in T cells and proper rearrangements of the T cell receptor. The latter is additionally based upon a promoter-enhancer 3D chromatin network directly mediated by SATB1. The regulatory SATB1 loops represent a refined layer of genome organization built upon a high-order structural scaffold established by conventional genome organizers such as CTCF. Apart from the T cell receptor locus, SATB1- mediated regulatory chromatin loops control expression of receptor and master regulator genes (such as Bcl6), collectively being critical for cell lineage specification and immune system homeostasis. The regulatory consequences of SATB1 roles in T cells were implied from Satb1fl/flCd4-Cre+ conditional knockout animals. They had vastly deregulated transcription and splicing, resulting in severe physiological aberrations resembling autoimmunity. Our data provide molecular mechanisms to explain the autoimmune phenotype of knockout animals. The described principles and regulatory mechanisms may be useful in conquering numerous human disorders including autoimmune diseases and cancer.
Language English
Subject Adaptive immunity
Chromatin organization
Chromosome X silencing
Nuclear matrix
Phase separation
T cells
Διαχωρισμός φάσεων
Επίκτητη ανοσία
Πυρηνική μήτρα
Τ Λεμφοκύτταρα
Χρωματινική οργάνωση
Χρωμόσωμα Χ
Issue date 2022-03-30
Collection   School/Department--School of Sciences and Engineering--Department of Biology--Doctoral theses
  Type of Work--Doctoral theses
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