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Epigenome Remodelling

Detailed locus-specific analysis of differentially methylated regions (DMRs) can yield information relating to differentiation stage specific changes in DNA methylation levels that may relate to finely regulated gene expression changes. In this instance, a DMR within the body of the murine Bcl2 gene (highlighted by the red box) is subject to demethylation specifically upon differentiation into the MPP2 cell state.

De-regulation of epigenome programming is a central hallmark of aging and is therefore interesting to study as both a causal driver of age-associated phenotypes and as a biomarker of the aging process. Starting from our previous manuscript from 2014, which documented DNA methylation programming events that occur during early hematopoietic differentiation [1], we have continued our long-standing collaboration with the group of Dr. Daniel Lipka (DKFZ Research Topic B) to analyze the DNA methylome of hematopoietic stem cells (HSCs) and their differentiated progeny in the context of malignant and non-malignant hematopoiesis using highly sensitive methodologies. This has allowed us to contribute towards studies which examine the mechanistic basis for DNA methylation programming during lineage specification of immune cells [2], as well as identifying a therapeutic vulnerability to DNA hypomethylating agents within acute myeloid leukemia (AML) stem cells, as well as pre-malignant human HSCs, that harbor common mutations in the de novo DNA methyltransferase, DNMT3a [3]. We have also leveraged DNA methylome data to act as a "epigenetic clock" in order to formally demonstrate that exposure to inflammation in early life results in accelerated biological aging of murine HSCs, as well as leaving a permanent epigenetic memory of this challenge within HSCs that correlates with their irreversible functional attrition [4].

  1. Cabezas-Wallscheid et al., Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome and DNA methylome analysis. Cell Stem Cell 15(4):507-522 (2014)
  2. Czeh et al., DNMT1 deficiency impacts on plasmacytoid dendritic cells in homeostasis and autoimmune disease. J. Immunol. 208(2):358-370 (2022)
  3. Scheller et al., DNMT3AR882 mutations in Clonal Hematopoiesis and Acute Myeloid Leukemia specifically sensitize cells to Azacytidine via endogenous retrovirus and Interferon network activation. Nat. Cancer 2:527-544 (2021)
  4. Bogeska et al., Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging. Cell Stem Cell 29(8):1273-1284 (2022)


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