Patientenkolloquium 2019
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AG PD Dr. O. El Maarri


Epigenetic and human disease
The idea of Epigenetic control of gene expression is becoming more prominent in the scientific literature. In its broad definition it includes all factors that could alter the gene expression profile of a particular gene or a group of genes without alteration in their DNA sequence. This definition include a broad range of human diseases, were tumours occupy a central position. Different type of tumors are characterised by alteration of gene expression and by landmarks of methylation changes at many loci. My group is interested in characterisation of these alterations.

The analysis of DNA methylation play here a central role to decipher the presence of methylation changes associated with abnormally expressed genes. The majority of methylation in human is present at 5 carbon position of CpG dinucleotides. To accurately quantify the methylation levels at specific CpG sites my group had developed an accurate and sensitive method based on bisulfite modification of DNA which is able to analyse as little as 40 ng of materials. This method that we call SIRPH (Single nucleotide primer extension - Ion Paired - Reverse Phase- HPLC) is based on bisulfite treatment of DNA followed by PCR amplification, than a single nucleotide primer extension is performed that is followed by direct separation on HPLC (El-Maarri et al, 2002). A flowchart description of the method is given in figure 1.

Figure 1: Flowchart of the SIRPH reaction for accurate quantitative measurement of levels of methylation at selected CpG sites (PDF).

Regulation and variations in DNA methylation
In addition to variation in the level of DNA methylation found associated with human diseases, some 'Normal' polymorphic variations also exist. My group is working to characterise such variations in normal population. Therefore factors such as hormones associated with gender, polymorphisms in epigenetic genes (such as DNA methyltrasnferases and histones modification enzymes) and copy number of X-Chromosome are being investigated.

Investigation of new mechanisms for F8 deficiency (causing hemophilia A)
In the healthy population the F8 activity levels are variable. It is known that high levels of F8 activity expose to a higher risk for thrombosis, while extreme low levels cause haemophilia. Studying large number of about 2400 haemophilia A patients that count for 1/3 of all patients in Germany we previously identified a unique cohort of a small percentage of patients (3% or about 80 individuals) with no mutations in the coding sequence of F8 (El-Maarri et al, 2005). We proposed earlier that in some of these patients a very low expression of F8 could be responsible for the haemophilia phenotype (El-Maarri et al, 2006). In Figure 2 the detailed mRNA expression analysis that show the expression of only one allele in one of the families is illustrated.

My group together with Prof. J. Oldenburg are following this work. We will address other potential mutations mechanisms by Southern blot, mRNA analysis and small/micro RNAs together with other coagulation parameters that could influence the variability of the F8 levels in plasma. In addition abnormal rearrangements or mutations inside the F8 introns will be investigated by sequencing of the entire F8 genomic region.

Our study will results in an improved understanding of novel mechanisms that lead to variability of F8 levels in normal and disease conditions.

Figure 2: Pedigree of the family were we could prove that one allele (GA) is not represented on the mRNA level that indicate lack of expressed or rapid degradation.

Ongoing research projects:

  • Characterization of novel mutation mechanisms leading to factor VIII deficiency.
  • Studying line-1 methylation levels globally and at specific loci in healthy and tumor samples.
  • Investigating the effect of anneuploidies on the epigenetic changes in human cells and determining the mechanisms that lead to such changes.
  • Determining molecular factors that give endothelial cells the ability to synthesize and secrete factor VIII.
  • Studying the link between NLRP7 mutations and the epigenetic changes observed in hydatidiform molar disease.


The Group
PD Dr. Osman El Maarri
Heike Singer (PhD Candidate)
Nicole Zimmer (MTA)
Amit Sharma (Guest scientist)

Stand: 06.11.2013