Modifications of collagen and chromatin in ECM-related disease: Uncovering therapeutic targets for fibrosis and cancer

Rutger Almer Friso Gjaltema

Modifications of collagen and chromatin in ECM-related disease: Uncovering therapeutic targets for fibrosis and cancer

Rutger Almer Friso Gjaltema

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De extracellulaire matrix (ECM) is essentieel voor vele biologische functies en wordt strikt gereguleerd vanaf transcriptie tot post-translationeel niveau. Wanneer deze balans verstoord wordt kunnen er verscheidene ECM-gerelateerde ziekten ontstaan. Fibroproliferatieve aandoeningen, zoals weefselfibrose en tumoren, worden gekarakteriseerd door excessieve productie van het ECM eiwit collageen type I door myofibroblasten. Tevens, in onomkeerbare fibrose bevat collageen type I buitenproportioneel veel pyridinoline cross-links die de collageen fibrillen onafbreekbaar maken en zo weefselregeneratie in de weg zitten. Zodoende zijn fibroproliferatieve aandoeningen een enorme last voor de zorgsystemen wereldwijd en is er veel belang bij het ontwikkelen van nieuwe effectieve therapeutische behandelingen. De doelstelling van dit proefschrift was om meer inzicht te geven in het ontstaan van fibroproliferatieve aandoeningen, door meer te weten te komen over de moleculaire processen die betrokken zijn bij myofibroblast differentiatie, collageen biosynthese, en collageen cross-linken. Zo hebben we transcriptionele en post-translationele processen in kaart gebracht die van belang zijn voor het genereren van functioneel lysyl hydroxylase 2, het enzym dat zorg draagt voor pyridinoline cross-linking. Tevens identificeerden we een aantal chromatine-modificerende enzymen die de transcriptie beïnvloeden van genen die een rol spelen in diverse profibrotische processen. Als laatste hebben we biotechnologische tools ontwikkeld die we met succes hebben gebruikt om de transcriptionele activiteit van ziekte-gerelateerde genen langdurig aan te passen. De bevindingen in dit proefschrift zorgen niet alleen voor het beter begrijpen van fibrotische processen, maar bieden tevens nieuwe therapeutische mogelijkheden die van groot belang kunnen zijn voor het overkomen van ECM-gerelateerde ziekten.

Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Bank, Ruud, Supervisor Rots, Marianne, Supervisor
Datum van toekenning	9-nov.-2016
Plaats van publicatie	[Groningen]
Uitgever	Rijksuniversiteit Groningen
Gedrukte ISBN's	978-90-367-9195-3
Elektronische ISBN's	978-90-367-9194-6
Status	Published - 2016

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Title and contents Final publisher's version, 268 KB
Chapter 1 Final publisher's version, 738 KB
Chapter 2 Final publisher's version, 1,05 MB
Chapter 3 Final publisher's version, 1,54 MB
Chapter 4Final publisher's version, 1,17 MB
Chapter 5 Final publisher's version, 1,54 MB
Chapter 6 Final publisher's version, 1,19 MB
Chapter 7 Final publisher's version, 1,97 MB
Chapter 8 Final publisher's version, 4,13 MB
Chapter 9 Final publisher's version, 5,76 MB
Chapter 10 Final publisher's version, 128 KB
Chapter 11 Final publisher's version, 61,7 KB
Appendices Final publisher's version, 82,6 KB
Complete thesisFinal publisher's version, 19 MB
PropositionsFinal publisher's version, 49 KB

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@phdthesis{4178e6eda069494da2aca215fcbdaa10,

title = "Modifications of collagen and chromatin in ECM-related disease: Uncovering therapeutic targets for fibrosis and cancer",

abstract = "The extracellular matrix (EM) is essential to many biological functions, and is tightly regulated from the transcriptional level to the post-translational level. When this balance is disturbed, several ECM-related diseases can arise. Fibroproliferative pathologies, such as tissue fibrosis and solid tumors, are characterized by excessive production of the ECM protein collagen type I by myofibroblasts. Additionally, in irreversible forms of fibrosis, collagen type I contains extensive pyridinoline cross-links which essentially prevent the collagen fibrils from being degraded, thereby hampering subsequent tissue regeneration. Fibroproliferative pathologies pose an enormous burden on health-care systems worldwide, and urge the development of effective therapeutic strategies. The aim of this thesis was to provide a better understanding of the development of fibroproliferative pathologies by addressing the molecular processes underlying myofibroblast differentiation, collagen biosynthesis and collagen cross-linking. We dissected the transcriptional and post-translational processes needed to generate the pyridinoline cross-linking enzyme lysyl hydroxylase 2. Furthermore, we identified several chromatin-modifying enzymes that influence the transcriptional regulation of genes involved in various profibrotic processes. Finally, we developed innovative biotechnological tools that were successfully exploited to interfere with the transcriptional activity of disease-related genes by modulation of their epigenome. The findings discussed in this thesis not only provide a better understanding of fibrotic processes in general, but also offer several novel avenues that could aid tremendously to overcome these ECM-related diseases.",

author = "Gjaltema, {Rutger Almer Friso}",

year = "2016",

language = "English",

isbn = "978-90-367-9195-3",

publisher = "Rijksuniversiteit Groningen",

school = "University of Groningen",

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TY - BOOK

T1 - Modifications of collagen and chromatin in ECM-related disease

T2 - Uncovering therapeutic targets for fibrosis and cancer

AU - Gjaltema, Rutger Almer Friso

PY - 2016

Y1 - 2016

N2 - The extracellular matrix (EM) is essential to many biological functions, and is tightly regulated from the transcriptional level to the post-translational level. When this balance is disturbed, several ECM-related diseases can arise. Fibroproliferative pathologies, such as tissue fibrosis and solid tumors, are characterized by excessive production of the ECM protein collagen type I by myofibroblasts. Additionally, in irreversible forms of fibrosis, collagen type I contains extensive pyridinoline cross-links which essentially prevent the collagen fibrils from being degraded, thereby hampering subsequent tissue regeneration. Fibroproliferative pathologies pose an enormous burden on health-care systems worldwide, and urge the development of effective therapeutic strategies. The aim of this thesis was to provide a better understanding of the development of fibroproliferative pathologies by addressing the molecular processes underlying myofibroblast differentiation, collagen biosynthesis and collagen cross-linking. We dissected the transcriptional and post-translational processes needed to generate the pyridinoline cross-linking enzyme lysyl hydroxylase 2. Furthermore, we identified several chromatin-modifying enzymes that influence the transcriptional regulation of genes involved in various profibrotic processes. Finally, we developed innovative biotechnological tools that were successfully exploited to interfere with the transcriptional activity of disease-related genes by modulation of their epigenome. The findings discussed in this thesis not only provide a better understanding of fibrotic processes in general, but also offer several novel avenues that could aid tremendously to overcome these ECM-related diseases.

AB - The extracellular matrix (EM) is essential to many biological functions, and is tightly regulated from the transcriptional level to the post-translational level. When this balance is disturbed, several ECM-related diseases can arise. Fibroproliferative pathologies, such as tissue fibrosis and solid tumors, are characterized by excessive production of the ECM protein collagen type I by myofibroblasts. Additionally, in irreversible forms of fibrosis, collagen type I contains extensive pyridinoline cross-links which essentially prevent the collagen fibrils from being degraded, thereby hampering subsequent tissue regeneration. Fibroproliferative pathologies pose an enormous burden on health-care systems worldwide, and urge the development of effective therapeutic strategies. The aim of this thesis was to provide a better understanding of the development of fibroproliferative pathologies by addressing the molecular processes underlying myofibroblast differentiation, collagen biosynthesis and collagen cross-linking. We dissected the transcriptional and post-translational processes needed to generate the pyridinoline cross-linking enzyme lysyl hydroxylase 2. Furthermore, we identified several chromatin-modifying enzymes that influence the transcriptional regulation of genes involved in various profibrotic processes. Finally, we developed innovative biotechnological tools that were successfully exploited to interfere with the transcriptional activity of disease-related genes by modulation of their epigenome. The findings discussed in this thesis not only provide a better understanding of fibrotic processes in general, but also offer several novel avenues that could aid tremendously to overcome these ECM-related diseases.

M3 - Thesis fully internal (DIV)

SN - 978-90-367-9195-3

PB - Rijksuniversiteit Groningen

CY - [Groningen]

ER -

Modifications of collagen and chromatin in ECM-related disease: Uncovering therapeutic targets for fibrosis and cancer

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