Seeing through the dark - dissecting the molecular determinants of lamina-heterochromatin interactions using the mouse retina

• Applicant: Dr. Michael Robson
• Subject Area: General Genetics and Functional Genome Biology ; Developmental Biology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 556274722

How the 3D structure of the genome regulates gene expression is crucial for cell-fate decisions and differentiation. Key to genome structure is the nuclear lamina which physically anchors heterochromatin to the nuclear periphery while euchromatin occupies the nuclear interior. Many studies indicate that lamina-attachments supports gene silencing and so their disruption impairs differentiation and causes disease. Yet, it remains unclear what mechanisms govern lamina-attachment or enable it to regulate gene activity.This fundamental gap in knowledge arises from challenges to manipulate genome-lamina interactions in vivo or directly measure their functional consequences. Here, we will overcome these limitations using in vivo scDam&T, a recent multi-omics method that jointly maps genome-lamina interactions and transcription in the same cell within complex tissues. We will apply scDam&T in vivo to the mouse retina, a unique model where heterochromatin-attachment is completely absent in mature cells but can be ectopically restored by expressing different lamina-attachment proteins. By quantifying chromatin dynamics and transcription in this controlled setting, we aim to uncover the hidden rules and functions of lamina-attachment.We will apply scDam&T to in vivo mouse models in four work packages. First, we will identify the genomic targets of lamina-attachment proteins by profiling the loci that they ectopically reattach to the lamina in mutant rod cells. Second, we will distinguish opposing models of lamina-attachment by mapping the order and timing of heterochromatin-release in wildtype maturing retinas. Finally, we will determine the functional consequences of lamina-attachment. We will use scDam&T’s joint transcriptomic readout to determine how losing or synthetically restoring lamina-heterochromatin interactions impacts gene expression. We will also profile parallel changes to cis-regulatory elements that control genes using single cell ATAC-seq. Finally, behavioural tests will also be performed in living mice to determine the impact of altered lamina-interactions on retina function an animal vision.Collectively, this work will provide an unparalleled mechanistic view of the most prominent but least understood component of chromatin structure, the nuclear lamina. In doing so, it holds the promise of unravelling how the lamina regulates our genomes and can contribute to human health and disease.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Marius Ader