Potential energy landscapes reveal the information-theoretic nature of the epigenome

ABSTRACTEpigenetics is defined as genomic modifications carrying information independent of DNA sequence heritable through cell division. In 1940, Waddington coined the term “epigenetic landscape” as a metaphor for pluripotency and differentiation, but epigenetic potential energy landscapes have not yet been rigorously defined. Using well-grounded biological assumptions and principles of statistical physics and information theory, we derive potential energy landscapes from whole genome bisulfite sequencing data that allow us to quantify methylation stochasticity genome-wide and discern epigenetic differences using Shannon’s entropy and the Jensen-Shannon distance. We discover a “developmental wheel” of germ cell lineages and an association between entropy and chromatin structure. Viewing methylation maintenance as a communications system, we introduce methylation channels and show that higher-order chromatin organization can be predicted from their informational properties. Our results provide a fundamental understanding of the information-theoretic nature of the epigenome and a powerful methodology for studying its role in disease and aging.

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Faculty Opinions recommendation of Potential energy landscapes identify the information-theoretic nature of the epigenome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727446576.793540898 ◽

2017 ◽

Author(s):

Wolfgang Fischle ◽

Alaguraj Veluchamy

Keyword(s):

Potential Energy ◽

Energy Landscapes ◽

Information Theoretic ◽

Potential Energy Landscapes

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Focal disruption of DNA methylation dynamics at enhancers in IDH-mutant AML cells

Leukemia ◽

10.1038/s41375-021-01476-y ◽

2021 ◽

Author(s):

Elisabeth R. Wilson ◽

Nichole M. Helton ◽

Sharon E. Heath ◽

Robert S. Fulton ◽

Jacqueline E. Payton ◽

...

Keyword(s):

Dna Methylation ◽

Myeloid Leukemia ◽

Bisulfite Sequencing ◽

Sequencing Data ◽

Genome Wide ◽

Cd34 Cells ◽

Recurrent Mutations ◽

Genome Bisulfite Sequencing ◽

Bisulfite Sequencing Data ◽

Acute Myeloid

AbstractRecurrent mutations in IDH1 or IDH2 in acute myeloid leukemia (AML) are associated with increased DNA methylation, but the genome-wide patterns of this hypermethylation phenotype have not been comprehensively studied in AML samples. We analyzed whole-genome bisulfite sequencing data from 15 primary AML samples with IDH1 or IDH2 mutations, which identified ~4000 focal regions that were uniquely hypermethylated in IDHmut samples vs. normal CD34+ cells and other AMLs. These regions had modest hypermethylation in AMLs with biallelic TET2 mutations, and levels of 5-hydroxymethylation that were diminished in IDH and TET-mutant samples, indicating that this hypermethylation results from inhibition of TET-mediated demethylation. Focal hypermethylation in IDHmut AMLs occurred at regions with low methylation in CD34+ cells, implying that DNA methylation and demethylation are active at these loci. AML samples containing IDH and DNMT3AR882 mutations were significantly less hypermethylated, suggesting that IDHmut-associated hypermethylation is mediated by DNMT3A. IDHmut-specific hypermethylation was highly enriched for enhancers that form direct interactions with genes involved in normal hematopoiesis and AML, including MYC and ETV6. These results suggest that focal hypermethylation in IDH-mutant AML occurs by altering the balance between DNA methylation and demethylation, and that disruption of these pathways at enhancers may contribute to AML pathogenesis.

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