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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 |
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Author
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Zelenka, Tomáš
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Thesis advisor
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Σπηλιανάκης, Χαράλαμπος
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Reviewer
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Γαρίνης, Γεώργιος
Strouboulis, John
Μαυροθαλασσίτης, Γεώργιος
Ταλιανίδης, Γιάννης
Θάνος, Δημήτρης
Δελιδάκης, Χρήστος
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| 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.
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| Language |
English |
| Subject |
Adaptive immunity |
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Autoimmunity |
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Bcl6 |
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CTCF |
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Cancer |
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Chromatin organization |
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Chromosome X silencing |
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Enhancer |
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Epigenetics |
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Hi-C |
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HiChIP |
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Immunoglobulin |
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Nuclear matrix |
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Phase separation |
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Prion |
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T cells |
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TCR |
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Thymocytes |
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Xist |
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Ανοσοσφαιρίνη |
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Αυτοανοσία |
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Διαχωρισμός φάσεων |
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Ενισχυτής |
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Επίκτητη ανοσία |
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Επιγενετική |
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Θυμοκύτταρα |
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Καρκίνος |
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Πριον |
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Πυρηνική μήτρα |
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Σίγηση |
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Τ Λεμφοκύτταρα |
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Χρωματινική οργάνωση |
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Χρωμόσωμα Χ |
| Issue date |
2022-03-30 |
| Collection
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School/Department--School of Sciences and Engineering--Department of Biology--Doctoral theses
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Type of Work--Doctoral theses
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| Permanent Link |
https://elocus.lib.uoc.gr//dlib/1/5/7/metadata-dlib-1645094620-952995-21840.tkl
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| Views |
476 |
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