Nuclear abnormalities such as nuclear blebs and micronuclei have devastating consequences for the genetic material and are associated with cancer or ageing. Scientists now revealed that the epigenetic enzyme MOF is crucial for the morphological integrity of the mammalian nucleus. Moreover, the study characterized the epigenetic landscape of nuclear abnormalities and discovered a formerly unknown epigenetic mechanism that seems to protect cells from additional damage.
Nuclear shape abnormalities are frequently observed in human diseases like cancer. Specifically, nuclear abnormalities called micronuclei (small nuclear structures in proximity to the main nucleus) and nuclear blebs (protrusions of the main nucleus) can lead to a severe impact on genomic DNA integrity. These abnormalities have historically been used as a diagnostic and prognostic tool for several cancers, such as breast cancer. Nevertheless, the precise molecular mechanisms behind their formation are not fully understood.
Absence of MOF causes a stochastic loss of nuclear shape
In their latest study, the lab of Max Planck director Asifa Akhtar discovered a spontaneous accumulation of micronuclei and nuclear blebs in primary cells after the loss of the epigenetic regulatory enzyme called MOF. This well-characterized enzyme facilitates the accessibility of genetic material by modifying histones, which are the proteins on which the DNA is wrapped around within the nucleus. «MOF deposits acetyl-groups on the histones. This opens the chromatin, the packaging of the DNA, and enables gene activity and thus the encoding of proteins. We wondered what could be the link between the classical epigenetic regulator MOF and the abnormal nuclear blebs and micronuclei,» explains Asifa Akhtar.
To investigate this question, her team, led by PhD student Adam Karoutas, performed an unbiased identification of the full spectrum of proteins which are acetylated by MOF in the cell. Their analysis revealed that MOF targets not only histone proteins but also the nuclear lamina protein Lamin A/C. Furthermore, the team identified the MOF associated NSL complex responsible for Lamin A/C acetylation. Lamin A/C is one of the building blocks of the mesh-structured nuclear lamina that acts as a viscoelastic shell for the nucleus. The study revealed that loss of Lamin A/C acetylation results in softened nuclei that are prone to mechanical pressure and eventually to breaking. Nuclear blebs and micronuclei are far more likely to be formed under these conditions.
Genomic breakdown in the nucleus
«These nuclear blebs and segregated micronuclei pose a risk to the integrity of cell’s genetic material. When we sequenced the genomic DNA of the primary cells that lack MOF, we found a battle ground,» says Adam Karoutas, the first author of the publication.
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