Nuclear envelope regulation of tissue-specific genome organisation, nuclear mechanics, signaling, and pathogen infection

The nuclear envelope (NE) is a central cellular hub that integrates signals to switch or fine-tune gene expression programs. it does so through 1) NE tethering of genome regions to generate differential subdomains with bound chromatin mostly silenced, 2) sequestering transcription factors, 3) controlling positioning of regulatory RNA-encoding loci, 4) regulating transport of factors into the nucleus, 5) NE-cytoskeletal connections integrating mechanical signals. Additionally, NE tethers flanking released genes influence the ability of the released genes to associate with superenhancers to achieve higher levels of expression¹. Each tissue has a distinct genome organisation pattern that optimises gene expression for that tissue’s needs and tissue-specific NE transmembrane proteins (NETs) direct tissue-specific gene repositioning. We mapped NET-dependent NE-genome contact changes during myogenesis, adipogenesis, in liver, and during lymphocyte activation^{1-2 and PMIDs:27264872,33330474}. In each system important differentiation/metabolic genes fail to reposition/regulate expression with loss of the tissue-specific NET yielding defective tissue differentiation, which we recapitulated in mice. Moreover, we found point mutations in these NETs that cause variants of human muscular dystrophy^{PMID:31862442}. NE-cytoskeletal connections are also critical for nuclear mechanics driving nuclear size changes and migration in development and cancer³ and several NE proteins are hijacked by viruses for replication/trafficking^{PMIDs:30717447,34541469} as well as contributing to integration/establishment of latency.

Research includes:

1. Testing NET disease point mutations for genome organisation defects and how genome changes are reflected in cell/tissue function in culture/mice.

2. Investigating composition and physics of genome-tethering complexes and how they are altered in disease.

3. Mapping non-disease muscle-damage genome changes in an in vitro system inducing damage with snake venom.

4. Using CRISPR/Cas9 to retarget loci to or away from the NE and/or engage large-scale deletions/insertions and visualise gene/enhancer movements with live-cell imaging.

5. Investigate NET involvement in cancer-type specific nuclear size changes linked to increased metastasis and test mechanisms of drugs that reverse the nuclear size changes, reducing cell migration/invasion.

6. Determine NE involvement in virus replication/egress e.g. NE proteins that support coronavirus replication/NEproteins involved in herpesvirus fusion to escape the nucleus.

7. Mapping HIV integration sites to understand how genome organisation influences the ability to activate from latency.

Creative ideas for additional directions will also be entertained so long as they involve tissue-specific functions of NE proteins.

Training outcomes:

The student will learn in vitro differentiation and/or mouse work, produce/analyse genome-wide DamID, Hi-C and RNA-Seq data, confirm such results by FISH/3C, and/or use CRISPR/Cas9 approaches or biochemistry for genome organisation projects. For other projects, super resolution microscopy, high-throughput drug screening, and virus handling are potential skills to develop.

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