Heterochromatin compartment remodeling in Autosomal Dominant adult-onset demyelinating LeukoDystrophy – ADLD

Autosomal Dominant adult-onset demyelinating Leukodystrophy (ADLD) is a genetic disease that leads to widespread damage to myelin, the protective covering of nerve cells in the central nervous system, with symptoms appearing in adulthood. This disease is caused by an excess of a protein called Lamin B1, which is a component of the nuclear lamina, a layer of proteins important for maintaining the structure of the cell nucleus. The nuclear lamina is also crucial to keep specific regions of DNA segregated at the nuclear periphery and to maintain them in an inactive, i.e. not transcribed, state.
We hypothesized that the Lamin B1 excess may disrupt the normal dynamics of these epigenetic regulatory interactions, leading to changes in the way DNA is organized and regulated. These dynamics are normally expected to change as people age, which may also explain why the disease starts in adulthood.
Our project will study the changes in DNA organization inside the cell nucleus and how its regulation is altered in ADLD patient cells. We will use advanced genomic techniques, including experimental methods developed in our laboratory, and special cell models of ADLD to study how the 3D structural organization of DNA changes in the disease. We will then look more closely at how these changes affect the epigenetic state of specific regions of the genome, possibly impacting the activity of genes and pathways.
By understanding the molecular events that lead to ADLD, we aim to identify new therapeutic targets in the disrupted epigenetic regulation processes.