The role of acetylation in the regulation of antimicrobial peptide gene expression in the human ...

309 Pages·2016·15.28 MB·English

by  Natalie Fischer

The role of acetylation in the regulation of antimicrobial
peptide gene expression in the human intestine
Natalie Fischer
To cite this version:
Natalie Fischer. The role of acetylation in the regulation of antimicrobial peptide gene expression
in the human intestine. Microbiology and Parasitology. Université Pierre et Marie Curie - Paris VI,
2014. English. ￿NNT: 2014PA066276￿. ￿tel-01371241￿
HAL Id: tel-01371241
https://theses.hal.science/tel-01371241
Submitted on 25 Sep 2016
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Unité de Pathogénie Microbienne Moléculaire
THÈSE
Présentée à
L’Université Pierre et Marie Curie

Ecole doctorale : ED515 « Complexité du Vivant »
“The role of acetylation in the regulation of antimicrobial peptide
gene expression in the human intestine”
Par Natalie Fischer
Thèse de doctorat de microbiologie
Dirigée par Philippe Sansonetti
Présentée et soutenue publiquement le 23 Septembre 2014
Devant un jury composé de :
ARLET, Guillaume Professeur à l’UMPC (Président du jury)
CERF-BENSUSSAN, Nadine DRCE INSERM (Rapporteur)
AIT-SI-ALI, Slimane DR2 CNRS (Rapporteur)
SANSONETTI, Philippe Professeur au Collège de France (Directeur de Thèse)
SPERANDIO, Brice CR1 INSERM (Co-directeur de Thèse)
Acknowledgements

Acknowledgments

First of all, I want to thank Philippe Sansonetti for flying me in from San Francisco to
interview and giving me the change to conduct a thesis in his laboratory. I enjoyed
very much the scientific discussions, which we shared over my project and his input
in my work. Also I want to thank him for the excellent resources concerning working
conditions as well as education, which are provided in his lab. I am very thankful to
have had the chance to work in the presence of his scientific genius and kindness
and I am grateful for his support throughout my thesis and afterwards.

I want to thank Brice Sperandio for being my close supervisor for the past years. He
guided me with the perfect balance of supervision, helped me settle in into the lab
and project in the beginning, and later trusted me to walk on my own feet. I learned a
lot from him, in the wet lab, but also concerning scientific writing and preparation of
presentations. I am thankful that he respected my opinion and critics, encouraged my
ideas and always had my best interest in mind. I am happy to say, that I think we
made a good team and he really did a great job with me.

I especially want to thank everybody who agreed to be on my thesis jury, for their
time and interest in my work. Special thanks go to Nadine Cerf-Bensussan and
Slimane Ait-Si-Ali for taking the time to read and correct my work and to Guillaume
Arlet, who kindly accepted to be the president of my jury. I am very much looking
forward to discuss my work with you!

My time at the Sansonetti lab would not have been the same without the friendly
atmosphere at PMM. I want to thank all my colleagues for their support, be it
scientific discussions, technical help in the lab or mental with the beer after work.
Especially I want to thank Emmanuel Sechet for his help in the last months, I could
have never done all those Western Blots without him.
Acknowledgements

I would not have been here if it wasn’t for the EIMID ITN program, who gladly
accepted me as a fellow. I enjoyed so much the international environment of this
program. In this regard, I want to thank especially Marco Bargagna, who was always
helpful and supportive, when it came to organizational things and deliverables. Also I
want to thank the great group of EIMID fellows, who really made these years of my
PhD special and with whom I enjoyed so many great times all around Europe.

I also want to thank my friends in Paris, especially the 12:30 lunch gang. Everybody
knows that science is a tough street and that especially during a PhD some breaking
points are reached. Thankfully I had a great support from my friends here at Pasteur
and I will never forget the times we shared in the ville de lumières. A special thanks
goes to Mathieu, who shared a very special year with me, and who has always was a
great support and source for laughter and good times.

My family deserves a great round of applause for always supporting me during all my
university education, morally and financially. I cannot thank you enough. I would not
be here today if it wasn’t for my Mum, Meikel, my uncle Dieter and my dearly missed
grandparents. This PhD title essentially goes to you!
List of Abbreviations

List of Abbreviations

1,25D3 – 1,25-dihydroxyvitamin D
3
AD – Atopic dermatitis
AMP – Antimicrobial peptide
ANG4 – Angiogenin 4
AP1 – Activator protein 1
APC – Antigen-resenting cell
APRIL – A proliferation-inducing ligand
ARE – Apical recycling endosome
ATF2 – Activating transcription factor 2
ATG16L1 – Autophagy related 16 like 1
ATP – Adenosine triphosphate
BAFF – B-cell activating factor
BMK – Big mitogen-activated protein kinase
Brd4 – Bromodomain-containing protein 4
CAMP – Cathelicidin antimicrobial peptide
CBP – cAMP-responsive element binding protein-binding protein
CCL20 – CC-chemokine ligand 20
CCR6 – CC-chemokine receptor 6
CD – Crohn’s disease
CDK9 – Cyclin-dependent kinase 9
CDRE – Caudal responsive element
CFTR – Cystic fibrosis transmembrane conductance regulator
CHD – Chromodomain-helicase-DNA-binding protein
CNV – Copy number variation
CNS1 – Conserved non-coding sequence 1
COPD – Chronic obstructive pulmonary disease
CRAMP – Cathelin-related antimicrobial peptide
CREB – Cyclic-AMP response element-binding protein
CRS – Cryptdins-related sequence
CTD – Carboxy‐terminal domain
CTLA-4 – Cytotoxic T-lymphocyte antigen 4
CXCR4 – C-X-C chemokine receptor type 4
DC – Dendritic cell
List of Abbreviations

DEFB1 – Human beta defensin 2
DEFB2 – Human beta defensin 2
DEFB3 – Human beta defensin 3
DEFB4 – Human beta defensin 4
DNA – Deoxyribonucleic acid
DNMT – DNA methyltransferases
E. coli – Escherichia coli
E. faecalis – Enterococcus faecalis
EGFR – Epithelial growth factor receptor
ER – Estrogen receptor
ERE – Estrogen-responsive element
ERK – Extracellular signal-regulated kinase
FAE – Follicle-associated epithelia
FliC – Flagella filament structural protein
FOXO – Forkhead box transcription factor
Foxp3 – Forkhead box P3
FRPL1 – Formyl peptide receptor-like 1
GALT – Gut-associated lymphoid tissue
GAS – Group A Streptococcus
GBS – Group B Streptococcus
GCN5 – General control non-repressible synthesis 5
GNAT – GCN5-related N-acetyltransferases
HAT – Histone acetyltransferase
HBO1 – HAT bound to Orc1
hCAP18 – Human cationic antibacterial protein of 18 kDa
HD 5 – Human alpha defensin 5
HD 6 – Human alpha defensin 6
HDAC – Histone deacetylase
HDACi – HDAC inhibitor
HDM – Histone demethylase
HIF1 – Hypoxia inducible factor 1
HIP/PAP – Hepatointestinal pancreatic/pancreatitis‐ associated
protein
HIV – Human immunodeficiency virus
HMT – Histone methyltransferase
List of Abbreviations

HNP – Human neutrophil peptide
HOTAIR – Homeobox antisense intergenic RNA
HPA axis – Hypothalamus–pituitary–adrenal axis
H. pylori – Helicobacter pylori
HSV – Herpes simplex virus
HRE – HIF1 responsive element
IAP – Intestinal alkaline phosphatase
IBD – Inflammatory bowel disease
IEC – Intestinal epithelial cell
IEL – Intraepithelial lymphocyte
IgA – Immunoglobulin A
IgG – Immunoglobulin G
IκBα – Inhibitor of NF-κB alpha
IKK – IκB kinase
IL8 – Interleukin 8
IL10 – Interleukin 10
IL1β – Interleukin 1 beta
ILF – Isolated lymphoid follicles
ILS – Insulin/insulin-like growth factor signaling
Imd pathway – Immune deficiency pathway
INF – Inflammatory gene
IRAK – Interleukin-1 receptor-associated kinase
IRF – Interferon response factor
ISWI – Imitation SWI
JDP – Jun dimerization protein
JNK – c-Jun N-terminal kinases
KCNN4 – Calcium-activated potassium channel protein 4
KDM2A – Lysine-specific demethylase 2A
Lgr5 – Leucine-rich repeat-containing G-protein coupled receptor 5
lincRNA – Large multi-exonic intervening non-coding RNA
LINoCR – LPS-inducible non-coding RNA
L. monocytogenes – Listeria monocytogenes
LPS – Lipopolysaccharide
LSD1 – Lysine-specific demethylase 1
LTi cells – Lymphoid tissue inducer cells
List of Abbreviations

mAchR – Muscarinic acetylcholine receptor
MAL – MYD88-adaptor-like protein
MAMP – Microbe-associated molecular pattern
MAPK – Mitogen-activated protein kinase
M cells – Microfold cells
MCP – Macrophage attractant protein
MDP – Muramyl dipeptide
MLN – Mesenteric lymph node
MOF – Males absent on the first
MORF – MOZ-related factor
MOZ – Monocytic leukemia zinc finger protein
MSK – Mitogen- and stress activated protein kinase
MSV – Multi site variations
M. tuberculosis – Mycobacterium tuberculosis
MUC-2 – Mucin 2
MYD88 – Myeloid differentiation primary response 88
nAchR – Nicotinic acetylcholine receptor
NCoR – Nuclear receptor corepressor
NEMO – NF-κB essential modulator
NFAT – Nuclear factor of activated T-cells
NF-κB – Nuclear factor kappa B
NK – Natural killer
NLR – NOD-like receptor
NOD – Nucleotide-binding oligomerization domain containing
protein
NuRD – Nucleosome remodeling deacetylase
p300 – E1A-associated protein of 300 kDa
P. aeruginosa – Pseudomonas aeruginosa
PCAF – p300/CBP-associated factor
PD1 – Programmed cell death protein 1
pDC – Plasmocytoid DC
PDF – Plant defensin
PGE2 – Prostaglandin 2
PGLYRP – Peptidoglycan recognition protein
PIC – Pre-initiation complex
List of Abbreviations

PLA2s – Secreted phospholipase A2
Pol II – RNA polymerase II
PP – Peyer’s patch
PPAR- γ – Peroxisome proliferator-activated receptor gamma
PRR – Pattern recognition receptor
PSA – Polysaccharide A
P-TEFb – Positive transcription elongation factor
REG3 – Regenerating islet-derived protein 3
RHD – Rel homology domain
RIP2 – Receptor-interacting protein 2
ROS – Reactive oxygen species
RNA – Ribonucleic acid
RTD – Rhesus teta defensin
SAGA – Spt-Ada-Gcn5 acetyltransferase
SAHA – Suberoylanilide hydroxamic acid
S. aureus – Staphylococcus aureus
SCFA – Short-chain fatty acid
SCTE – Stratum corneum tryptic enzyme
S. epidermidi s – Staphylococcus epidermidis
SFB – Segmented filamentous bacteria
S. flexneri – Shigella flexneri
SIGIRR – Single immunoglobulin IL1R-related molecule
Sirtuins – Silent information regulator 2-related proteins
SLP1 – SUN-like Protein 1
SLPI – Secretory leukocyte peptidase inhibior
SMRT – Silencing mediator of retinoic acid and thyroid hormone
receptors
SNP – Single nucleotide polymorphism
SOCS – Suppressor of cytokine signaling
SP1 – Specificity protein 1
S. pneumoniae – Streptococcus pneumoniae
STAT – Signal transducer and activator of transcription
S. typhimurium – Salmonella typhimurium
SWI/SNF – SWItch/sucrose non fermentable
TAD – Transactivation domain
List of Abbreviations

TF – Transcription factor
TGFβ – Transforming growth factor beta
Th cell – T helper cell
Tip60 – Tat-interacting protein of 60 kDa
TLR – Toll-like receptor
TNFα – Tumor necrosis factor alpha
TOLLIP – Toll interacting protein
TRAF – TNF receptor-associated factors
TRAM – TRIF-related adaptor molecule
Treg cell – Regulatory T cell
TRIF – TIR domain-containing adaptor protein inducing IFNβ
TSA – Trichostatin A
TSLP – Thymic stromal lymphopoietin
TSS – Transcriptional start site
UC – Ulcerative colitis
UHRF1 – Ubiquitin-like, containing PHD and RING finger domains 1
VDR – Vitamin D receptor
VDRE – Vitamin D responsive element
Wnt – Wingless-type
XPB – Xeroderma pigmentosum B
XBP1 – X-box binding protein 1
XIST – X-inactive specific transcript