Are rapidly proliferating cells epigenetically malleable?



Fig 1. Experimental design. Upper part: a schematic representation of the embryonic development of Xenopus laevis. Stages of development (NF) according to Nieuwkoop and Faber (1994). The steps used for mass spectrometry of histone changes and embryonic analyzes are characterized by the following characteristics: NF13 – late gastrula, germ layer specified; NF18 — neurula, structuring and differentiation of the germinal layer; NF25 — tail bud stage, organogenesis; NF32 – early tadpole, body plan established. Bottom part: We carry out 2 types of experiments: Type A experiment (G1 / S block) – embryos are divided into 2 groups, which from NF10.5 are continuously incubated in HUA solution or control solution (DMSO as a support). Type B experiment (transient arrest) – embryos are divided into 3 groups: Continuous Mock, Continuous HUA and Transient HUA. In the last group, the HUA solution is replaced at NF13 by the DMSO solution. DMSO, dimethylsulfoxide; HUA, hydroxyurea and aphidicolin; HUAwo, HUA wash. Credit: DOI: 10.1371 / journal.pbio.3001377 # sec010

DNA, the inherited material, interacts with proteins in the nuclei of cells to form a tightly packed complex with proteins called “chromatin”. The molecular architecture of chromatin regulates access to genes and therefore determines which genes can be turned on in different cell types. Various chemical modifications of proteins called histones, which play a key role in the structuring of chromatin, serve as markers that can activate or inhibit gene expression. How these epigenetic changes are regulated during development and in other contexts is not fully understood. Today, researchers led by LMU molecular biologist Ralph Rupp have shown that the process of cell division itself can have an impact on which changes become dominant. In rapidly dividing cells, the levels of inhibitory changes are reduced, increasing the likelihood of reactivation of silent genes. This phenomenon occurs in embryonic cells, and most likely in adult stem cells and precursor cells, as Rupp and colleagues report in the review. PLOS Biology.

Histone changes encode important information that helps ensure the orderly progression of early development. Using an established experimental model, the tadpole stage of the clawed toad Xenopus laevis, Rupp’s group was able to show that different histone changes become dominant at different stages of embryonic development. “To our surprise, we discovered that the cell cycle – the sequence of events that takes place in cells in the interval between one division and the next – has an impact on the profile of changes present in chromatin,” explains Rupp. “When cells switch between a resting and resting state and a proliferative state, in which cells divide more often, certain epigenetic markers are selectively altered.”

This is particularly true for repressive modifications, which silence genes. “Such modifications are apparently very sensitive to the so-called S-phase dilution effect,” explains Rupp. This effect results from the fact that during cell division, not only DNA, but chromatin as a whole must be replicated. While the existing histone proteins are evenly distributed among the replicated DNA strands, the newly synthesized histones – which have not yet been modified – fill in the gaps. This is because the degree of modification of the histones of the daughter chromosomes immediately after cell division is only half of what it was before DNA replication.

Observations made on the clawed toad demonstrate that the rate of cell proliferation exceeds the rate at which repressive changes in histones are synthesized in chromatin. An important implication of this is that genes which have already been inactivated return to a less repressed state once a cell decides to divide again. This in turn suggests that the properties of a given cell are more malleable than is generally assumed. “In contrast, in resting cells the total number of repressive markers increases – and at some point it reaches a level where specific genes become permanently inactivated,” says Rupp.

In addition to embryonic cells, this mechanism most likely plays an important role in adult stem cells and precursor cells, according to the study authors. They also suggest that it could possibly be used as a way to reprogram cells to make them more effective for specific therapeutic purposes.

Epigenetics: inheritance of epigenetic markers

More information:
Daniil Pokrovsky et al, Systemic cell cycle block impacts stage-specific histone modification profiles during Xenopus embryogenesis, PLOS Biology (2021). DOI: 10.1371 / journal.pbio.3001377 # sec010

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Quote: Molecular biology: Are rapidly proliferating cells epigenetically malleable? (2021, October 26) retrieved December 3, 2021 from

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