Local rewiring of genome - nuclear lamina interactions by transcription
Preprint posted on 27 June 2019 https://www.biorxiv.org/content/10.1101/685255v1
Article now published in EMBO Journal at https://www.embopress.org/doi/10.15252/embj.2019103159
Background & Summary:
The genome is spatially organised within each cell nucleus and this 3D conformation is important for gene regulation. Lamina-associated domains (LADs) are large chromatin regions that interact with the nuclear lamina in the interphase nucleus. These domains are associated with repressive functions, and genes located within LADs usually have low transcriptional activity. The contacts between LADs and the nuclear lamina are very stable in some cases and consistent between different cell types, while in other cases, there are cell-type specific interactions.
It was not clear if the link between repression of genes and interactions of these genes with the nuclear lamina was direct or something secondary. Very recently, the same lab showed that positioning LAD-associated promoters in a neutral context made them become active, suggesting that LADs form a repressive environment (Leemans et al. 2019). In this preprint, the authors forcedly activate or inactivate gene transcription in different contexts to test how this affects the contacts with the nuclear lamina.
Major experiments in the preprint:
- Activation of genes inside LADs by expressing the transcriptional activator VP64 targeted to selected promoters using a guideRNA.Activation of gene transcription caused detachment of chromatin from the nuclear lamina along the gene body. In some cases, this detachment expanded a bit to the flanking regions but it was mainly specific to the gene. A gain of nuclear lamina interactions in a nearby region was rarely observed but it was not consistent in order to determine whether there are compensatory rearrangements. When activating several genes within the same domain, detachments were still local, and they did not cause a more global detachment due to synergistic or cooperative effects.
- Inactivation of transcription by heterozygous deletion of promoters or insertion of a polyadenylation sequence. The authors targeted genes whose association to the nuclear lamina is dependent on the cell-type and therefore, changes in attachment are more likely to occur. An increase in nuclear lamina interactions could be observed specifically in the mutant allele while the wildtype remained unaffected. These re-attachments were also local and specific to the targeted genes.
- Insertion of an active transgene into a LAD. Similarly to the activation of endogenous genes, the integration sites showed a reduction of contacts with the nuclear lamina as compared to the corresponding wildtype sites.General comments and why I chose this preprint:The spatial organization of the genome within the nucleus is important for the regulation of gene expression. Recent works try to decipher if this is also important in the other direction and ask if transcription can modulate genome organization. As usually in biology, there is not a clear yes/no answer but there are nuances and different behaviours in different contexts and at different genomic scales. Recent studies showed that, in general, transcription is not required for global genome architecture, but could have a role at a local scale for the formation of subcompartments (reviewed in van Steensel and Furlong. 2019). The results of this preprint point to the same direction. Activation or inactivation of transcription leads to detachments and re-attachments of chromatin to the nuclear lamina, but mainly in a site-specific manner. The fact that there is an inherent layer of variability and context-dependent effects, assessing several strategies is key to get a better understanding. I like that Brueckner and colleagues use different approaches and complementary assays by activating and repressing transcription to get to their conclusions. The selection of DamID mapping of Lamin B1 interactions as a method to measure detachment and re-attachment to the nuclear lamina is key to interpret the results. It gives a detailed view not only of the specific gene but also of the flanking regions. Again, it is difficult to generalize but I think this work is important for the field to try to build a more general picture of how the genome is spatially organized based on different strategies and different contexts.
Questions to the authors
The authors mention that some interactions between LADs and the nuclear lamina are very stable between cell types while others are cell or tissue specific. The experiments that address transcriptional inactivation are performed in genes whose contacts are more susceptible to change given that they are different in mouse embryonic stem cells or in neural precursor cells. Have the authors tried to see what happens in LADs that are more stable between cell types? Are genes contained in those LADs always transcriptionally silenced? Or are there genes that are expressed in low but constant levels across different cell types that could be susceptible to transcriptional changes?
Leemans C, van der Zwalm MCH, Brueckner L, Comoglio F, van Schaik T, Pagie L, van Arensbergen J, van Steensel B. (2019). Promoter-Intrinsic and Local Chromatin Features Determine Gene Repression in LADs. Cell 177(4):852-864.
van Steensel B, Furlong EEM. (2019). The role of transcription in shaping the spatial organization of the genome. Nat Rev Mol Cell Biol 20(6):327-37.
Posted on: 15 July 2019 , updated on: 19 March 2020Read preprint
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