Several epigenetic pathways have been found to play a role in the spatial organisation of DNA during early embryonic development in mice.

An international research team investigated the formation of lamina-associated domains (LADs), which are areas of DNA that interact with the nuclear lamina, a structure that lines the inside of the nucleus. This was achieved using low-input genomics, which are techniques that require only small inputs of DNA, to gain insight into how mouse embryos establish this nuclear organisation. The researchers found that the presence of heterochromatin, histone modifications and histone content were essential for this process.

'Previously, it was not known whether a single central mechanism controlled nuclear organisation after fertilisation,' said Professor Maria-Elena Torres-Padilla, director of the Institute of Epigenetics and Stem Cells at Helmholtz Munich, Germany, and the senior author of this study published in Cell. 'Our results show that after fertilisation, multiple parallel regulatory pathways control nuclear organisation, reinforcing each other'.

The formation of LADs represents the earliest feature of nuclear organisation during embryo development in mammals. In the first hours after fertilisation, major changes in the organisation of DNA within the nucleus begin. It is known that epigenetics plays a key role in this process – gene activity is regulated by modifications to DNA and the proteins produced. The researchers aimed to identify the molecular factors responsible by disrupting epigenetic modifications and mapping the position of LADs.

'We wanted to understand how these epigenetic programmes influence gene activity and ensure that the cell correctly executes its developmental tasks,' explained Professor Torres-Padilla.

Results of the disruptions showed differences depending on the stage of the embryo. For example, modification of histones and the reduction of their overall number in the zygote stage disrupted the formation of LADs. This was then shown to be self-resolved by the two-cell stage, highlighting an ability of early embryos to amend mistakes within their nuclear organisation and implying that two-stage embryos are more resilient compared with their earlier counterparts.

Additionally, editing specific enzymes that are responsible for histone modifications resulted in changes to the association between the genome and the lamina. Within the two-cell stage, disruption of pathways involved in maintenance of heterochromatin, a tightly packed inactive version of DNA, or certain histones disrupted the organisation of LADs.

The authors highlight these results as a potential basis for further research into diseases such as progeria, a genetic disorder characterised by advanced ageing. Progeria is linked to a disruption of the association of DNA with the nuclear lamina. Furthermore, several cancers are linked to changes in DNA organisation with the nucleus.

Professor Torres-Padilla exaplined that these results 'Can help to better understand these mechanisms and, in the long term, develop new approaches to specifically influence epigenetic programmes to improve disease outcomes'.