Epigenetics: inheritance of epigenetic markers

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A study by an international team led by the Ludwig-Maximilians-Universitaet (LMU) in Munich, molecular biologist Axel Imhof, sheds new light on the mechanisms that control the establishment of epigenetic modifications on newly synthesized histones after division cellular.

The classical genetic code is not the only code involved in regulating cell differentiation and the behavior of multicellular organisms. Instructions encoded in the nucleotide sequence of genomic DNA determine which sets of genes are expressed in a given cell type. Their selective expression thus defines the differences between a muscle cell and a nerve cell, for example. However, there is a second level of control that helps regulate gene expression patterns. This is based on chemical modifications of DNA and the histone proteins it is packaged in. This epigenetic code is now recognized as a vital part of the process responsible for differentiating – and maintaining – different cell types in higher organisms, although virtually all of an individual’s cells carry the same complement of genetic information.

However, unlike DNA sequence replication itself, the transmission of epigenetic information during cell division is not well understood. Today, a team led by Axel Imhof at the LMU Biomedical Center, in collaboration with research groups based at Helmholtz Zentrum München and Denmark, has used a combination of theoretical modeling and experimentation to elucidate the mechanisms that mediate establishment of epigenetic marks after cell division. The results, which appear in the journal Cell reportsprovide deeper insight into the inheritance of epigenetic histone modifications.

In higher organisms, most of the DNA in cells is found in a condensed form called chromatin, in which the DNA is wrapped around particles made of proteins called histones. In chromatin, the functional state of a given gene largely depends on exactly how it is packaged. More specifically, the chemical modification of histones modulates the accessibility of DNA in chromatin and thus controls whether the proteins necessary for gene expression can actually bind to DNA. In order to ensure the stable transmission to daughter cells of gene expression patterns that define the identities of different cell types, it is crucial that chromatin states are maintained during cell division.

In the new study, Imhof and his colleagues focused on two specific histone H3 modifications, the methylation of lysines at positions 27 and 36 (K27me and K36me). The attachment of a methyl group (CH 3 ) to the histone modifies its binding affinity for regulatory proteins and modifies the degree of chromatin compaction. K27me is usually found on H3 in regions where genes are inactive, while K36me serves as a marker for active genes.

The crucial question addressed in the study was: what happens to these changes during cell division? Cell division is preceded by DNA replication, which doubles the amount of DNA to be packaged and therefore requires the synthesis of new histones. However, freshly synthesized histones do not carry any epigenetic modification. How do cells then ensure that the new histones acquire the correct pattern of modifications within the newly formed chromatin?

The problem is delicate and the experimental approach adopted to solve it was technically difficult. The team first labeled the newly synthesized histones with heavy (non-radioactive) isotopes. The new (heavy) histones could therefore be distinguished from the old (light) histones using high-resolution mass spectrometry. They then followed the fate of these two “generations” of histones in the daughter cells after cell division.

The patterns of change they observed were extremely complex. In order to make sense of them, they designed two models for the inheritance of histone epigenetic modifications and used a computational procedure to compare the theoretical modification models with the dynamic changes detected in their tagging experiments. In theory, each of the lysines at positions 27 and 36 in histone H3 can be modified with one, two or three methyl groups. This meant that 16 possible isoforms had to be considered.

“Based on our modeling studies, we were able to demonstrate that the methylation patterns of the two functionally antagonistic residues K27me and K36me in cells influence each other reciprocally”, explains Axel Imhof. “The patterns we actually observed can best be explained by the hypothesis that certain regions of the genome – which we call domains – exhibit definite patterns of methylation.” Another surprising finding was that, in rapidly dividing embryonic stem cells, the levels of demethylation observed during cell division were insignificant. The team now plans to investigate in more detail what precisely happens in these cells.

In the longer term, the researchers hope that their work will rapidly identify pathological alterations in the epigenetic states of cells. Tumor cells are known to often contain mutant forms of the enzymes responsible for the de novo changes that occur during cell division, and this appears to be associated with the increased proliferation rates seen in these cells. “Therefore, a lot of work is currently underway to develop ‘epidrugs’ that could modulate the activity of these enzymes,” says Imhof.


The two faces of cellular oblivion


More information:
Constance Alabert et al, Domain model explains propagation dynamics and stability of histone H3K27 and H3K36 methylation landscapes, Cell reports (2020). DOI: 10.1016/j.celrep.2019.12.060

Provided by the Ludwig Maximilian University of Munich

Quote: Epigenetics: Inheritance of epigenetic markers (2020, February 7) retrieved March 16, 2022 from https://phys.org/news/2020-02-epigenetics-inheritance-epigenetic-markers.html

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