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Summary 9 Caput lectures
- Instelling
- Universiteit Utrecht (UU)
Summary of the ninth lecture clinical immunology which were caput lectures about rheumatoid arthritis and single-cell analysis
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Clinical Immunology Evelien FloorHC9 Caput lectures
Epigenetic regulation in rheumatoid arthritis
Depending on the stimuli in the environment immune cells can change their phenotype. Epigenetics
regulates this. Epigenetics means that from the same DNA, genes are differentially expressed in
different cell types expressed at different levels at different times. Epigenetics is the branch of biology
which studies the causal interaction between genes and
their products, which brings the phenotype into being.
epigenetics can’t be transmitted from mother cell to
daughter cell.
DNA is wrapped around histones. To transcribe genes, the
DNA has to be opened. Genetics is identical regardless of
the cell type. Epigenetics is specific to a certain cell type
and sensitive to the environment. Environmental factors
are gender, viral infection, hormones, geography,
nutrition and chemicals. Genetics is stabile whereas
epigenetics is reversible.
Rheumatoid arthritis
RA is an illness of the joints. Fibroblast-like synoviocytes (FLS) provide nutrients to the joints. Patients
with rheumatoid arthritis develop autoantibodies (usually 15 years before clinical presentation),
causing an inflammation and destruction. What happens, is that the tissue is infiltrated with active
immune cells.
There are several reasons why to study epigenetics in RA. First of genetic polymorphisms explain 50-
60% of the disease risk. Secondly, there is also a gender bias, 70% of the patients is female. This is due
to differences in hormones. In healthy individuals there are only one or two layers present of FLS, in
RA this are more layers. So, the behaviour of FLS is imprinted. Lastly, RA is a relatively new disease
because it was first observed in 1800.
Epigenetic regulation
Modificators alter the genetic code, there are writers, erasers and readers. Writers are the kinases
who add phosphates to DNA or histones. Erasers are the phosphatases who take the modifications off.
Readers are proteins with SH2 domains who bind to phosphates. There are two types of modifications:
on DNA and histones.
DNA methylation
Methylation is the addition of a methyl group
to CpG dinucleotides who are predominantly
found in noncoding regions. CpGs are often
clustered near gene promoters: “CpG islands”.
There is one class of enzymes that adds the
methyl group: DNA methyltransferases
(DNMTs): DNMT1 for new DNA and
DNMT3A/B for de novo DNA methylation. If
DNA methylation occurs in transcription factor
binding sites it blocks the binding of the
transcription factors and thereby inhibits
transcription. On the other hand, methyl
groups can recruit transcriptional repressors.
This also inhibits transcription.
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, Clinical Immunology Evelien Floor
DNA methylation also occurs when the X chromosome
needs to be inactivated. An inactivated X chromosome is
only methylated in promotor regions. An active X
chromosome has much more DNA methylation over the
whole chromosome.
In RA, much less DNA methylation occurs compared to
osteoarthritis (OA) patients. normally, retroviral DNA
tends to be methylated to prevent its escape. However,
in RA patients there is expression of retroviral elements.
Also, when you treat OA patients with methylation
inhibitors, you get a much more RA phenotype.
Deregulated DNA methylation in immune-mediated inflammatory diseases can be caused by different
mechanisms. First of all, during ageing DNA methylation decreases. Therefore, autoimmunity is an age
depending event. There is also deregulation of enzymes regulating DNA methylation status (e.g.
decrease in DNMTs). Lastly, there can be miRNA deregulation which results in deregulation of other
epigenetic factors. Overexpression of certain miRNAs can result in hypomethylation by repression of
the expression of DNMT1.
Histone modifications
Polymorphisms that are abundant in RA are not occurring in coding regions but in super enhancers.
Many of those polymorphisms that occur in super enhancers are affecting the binding of transcription
factors and thereby gene transcription. Histone modifications are responsible for the transition from
heterochromatin (close) to euchromatin (open).
Histones 3 and 4 have long N-terminal tails that are available for modification. The mechanism behind
histones is that they are positively charged, and thereby interact with negatively charged DNA.
Modification of histones takes away the positive charge which differs the interaction with the DNA,
affecting transcription. Different modifications are: acetylation, phosphorylation, methylation and
ubiquitination.
Acetylation occurs on lysins, and methylation on arginines, mainly. Acetylation of lysine in histones is
associated with active gene transcription, whereas methylation is associated with repression of gene
transcription. Acetyltransferases add acetyl groups, whereas histone deacetylases (HDACs) take the
acetyl groups off. There are multiple classes of HDACs: 1 is present in every cell, 2 is cell specific (cycles
between nucleus and cytoplasm) and 4 is involved in longevity. HDACs were already present in early
bacteria, they evolved before histones. They also have more substrates than kinases. This indicates
that there are also non-histone targets.
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