Caput Epigenetics
27 important questions on Caput Epigenetics
Explain which mechanism causes the plasticity of macrophages.
Which two mechanisms determine epigenetics?
What factors influence epigenetics?
Explain the mechanism of the disease rheumatoid arthritis.
In established r.a., there are synovial villi, angiogenesis, eroded bone, pannus etc (in short; synovial membrane has changed). This is due to interaction between synoviocytes and leukocytes --> auto-antibodies against synoviocytes.
(Don't learn this in detail).
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Why should epigenetics be investigated in chronic inflammation (aka RA)?
2. gender bias (epigenetic modifications determine x-chrom inactivation)
3. hyperplastic synoviocytes (FLS) resemble solid tumors (so... behaviour cells is changed).
4. the pathogenic behavior of FLS is imprinted (epigenetic modifications determine imprinting).
Which three ways of epigenetic regulation do you know?
2. Transcriptional regulation by DNA metylation
3. Post transcriptional regulation by RNA interference
In which regions can you see DNA methylation?
How does DNA methylation regulate transcription?
- Methylation blocks binding of transcription factor on the nearby gene promotor.
- Methylation attrackts co-repressors
Which role does DNA methylation plays in Rheumatic Arthritis?
DNA methylation fingerprints distinguish RA synoviocytes (FSL) from OA (voorstadium, minder aggressief); shows hypomethylation in RA.
Which mechanisms deregulate DNA methylation in immunde mediated inflammatory disease?
- Aging: DNA methylation decreased during aging.
- Deregulation of enzymes regulation DNA methylation: DNMTs are decreased in SLE.
- Active DNA demethylation: AICDA promotes active demethylase (supress = medication for SLE).
- miRNA deregulation: miRNAs that promothe hypomethylation by repressing expression of DNMT1, are overexpressed in SLE.
How do (histone modifications of) superenhancers influence Rheumatic A?
Histone acetylation has influence on the function of these superenhancers?
(So is it due to polymorphism or due to histone modification?)
In what ways can gene expression be regulated by miRNA?
How is inhibition of gene expression by miRNA regulated?
So; when gene is transcribed (nice histones, no methyl), gene product is still inhibited.
What is observed in miRNA expression in immune mediated inflammatory disease?
Slides: "Inflammation (cytokines) regulates miRNA". This is the other way around?
How do epigenetics influence systemic sclerosis?
For example, miRNA681 overexpression in systemic sclerosis pDCs contributes to the type I interferon signature. This means that this miRNA overexpression causes overexpression of IFNalfa.
How do histone modifications regulate gene expression?
By which three types of proteins is the epigenetic code established, regulated and interpreted?
What are HDCAs? What is their funtion in regulation of gene expression?
Acetylation --> neutralization tails --> relaxing chromatin structure.
+acetyl=binding place bromodomains --> transcription.
Deacetylation --> chromatin compaction --> transcription repressed.
Why are HDCAs often kalled key signalling enzymes? Why is it important that this is further investigated?
Which role does HCAC play in arthritis?
- HDAC activity is high in RA synovial tissue (so; more deacetylation of different proteins; big influence....)
- TNFalfa increases HDAC activity/expression in RA.
- Pan-HDACi (=HDAC inhibitors) suppress cytokine production in vitro, ameliorate joint inflammation and prevents bone destruction in vivo (Givinostat = safe and effective).
Effect of inhibitors on cytokine production was measured "Both the selective and the nonselective HDAC inhibitors (MI192 and TSA, respectively) were found to regulate cytokine production from PBMCs, but their effects were cell type and compound specific"
TNFalfa increases HDAC activity... but HDACinhibitors regulate cytokines? So what is cause and what is consequence here?
What is the role of specific HDAC5 in RA?
What is the role of specific HDAC3 in RA?
Macrophages from Hdac3 -/- mice are unable to activate half of the inflammatory gene expression program because of reduced Stat1 expression levels (but HDAC only inflence phosphorylation and DNA binding of STAT, not the acetylation.....)
What is the function of bromodomain proteins in generegulation?
BRDs selectively recognize and bind to acetylated Lys residues - particularly in histones - and thereby have important roles in the regulation of gene expression.
Acetylation of Lys domains neutralizes the histones; euchromatine; transcriptional activation.
Explain what BET inhibitors are en how they are used in patients with RA
BET family inhibitors supress monocyte activation. iBET compound protects mice against infection-mediated inflammation.
Figure: Expression of genes regulated by TNF-α and IL-1β in RASF after cytokine stimulation in the presence or absence of the inhibitor. RASF exposure to BET inhibitors: more than 25% downregulation in the message levels of 70.2% and 73.1% of genes induced (more than twofold) by TNF-α and IL-1β, respectively. So BETi inhibits inflammation in RA.
Why is it important to distinguish different bromodomains?
Explain why ER stress can be used as a model for epigenetic regulation.
What role does ER stress play in RA FLS?
- ER stress enhances TLR4 signalling in the FLS (synoviocytes) and therefore activation of these cells in RA patienst.
- ER can modulate epigeneti regulatory proteins (in B27+ spA).
What can we use epigenetics for in immune mediated inflammatory disease?
- Refining omics data
- Diagnostics and prognostics
- Understanding pathobiology
- Therapeutic strategies.
Joint specific regulation of synoviocytes in RA.
Our data highlight the importance of the chromatin structure in regulating inflammatory processes in macrophages and different types of fibroblasts. This primes SF for an enhanced inflammatory and destructive response during repeated activation of TLR4. Future studies will show whether drugs targeting epigenetic enzymes are able to manipulate the sustained response of SF to TLR activation.
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