Eric Schirmer

Tissue-specific nuclear envelope organization in genome and nuclear size regulation: roles in inherited metabolic disorders, muscular dystrophy, and virus infection.

Professor Eric Schirmer started his scientific career in the lab of Niza Frenkel at the National Institute of Allergy and Infectious Diseases (USA) where he was part of the team that discovered the 7th human herpesvirus.  He then obtained his PhD in Molecular Genetics and Cell Biology at the University of Chicago, USA, in the lab of Susan Lindquist where he provided the first biophysical evidence for a direct interaction between yeast prions and chaperones. His Postdoc was done with Larry Gerace at the Scripps Research Institute, USA, where he studied roles of nuclear lamin structural proteins and identified many novel nuclear envelope transmembrane proteins (NETs). 

portrait photo of Eric Schirmer
Eric Schirmer

In September 2004, he joined the Wellcome Trust Centre for Cell Biology at the University of Edinburgh to start his own lab with the help of a Wellcome Trust Senior Research Fellowship. He first demonstrated that the nuclear envelope proteome is highly tissue-specific and identified hundreds of tissue-specific NETs. He then found several subsets of NETs involved in cell cycle regulation, cytoskeletal organisation, nuclear size regulation, tissue differentiation, and spatial genome organisation. 

Eric is currently the Personal Chair of Nuclear Envelope Biology at the Institute of Cell Biology and Centre for Cell Biology as well as Director of Internationalisation for the School of Biological Sciences with his current research mostly focused on the roles of tissue-specific NETs in genome organisation in development and disease, nuclear size misregulation in cancer, and NET roles in virus infections.

Dr Jose de las Heras, Qingqin Ji, Yuwen Gao, Rosina Graham, and Dr Xuefei Wang


Roles of Tissue-Specific NETs in development and disease

Mutations in widely expressed nuclear envelope (NE) proteins cause many distinct diseases with tissue-specific pathologies including muscular dystrophies, lipodystrophies, neuropathy, dermopathy, and premature-aging syndromes. This raised the question: how could mutations in the same ubiquitous protein cause distinct diseases affecting different tissues? Hypothesizing that tissue-specific partners mediate the tissue-specific pathologies, we identified candidate partners with proteomics. The NE connects on the inside to chromatin and genome organisation is disrupted in patient cells. If our hypothesis is correct, it follows that these tissue-specific NETs might direct tissue-specific patterns of genome organisation with consequences for gene expression and we have found this to be the case.

We found several muscle-specific NETs that re-position genes to the NE that are needed early in myogenesis, but subsequently become inhibitory and must be tightly shut down. Their combined knockdown blocks myogenesis. Thus, NE gene recruitment enables tighter regulatory control. Importantly, we found mutations in these muscle NETs in previously unlinked Emery-Dreifuss muscular dystrophy patients and these mutations block the gene-repositioning function of the NETs, further arguing the importance of this novel regulatory mechanism. We found similar effects with fat-specific NETs in adipogenesis and that mice lacking fat-specific NET Tmem120A have difficulty producing fat, become insensitive to insulin, have metabolic dysfunction and a general lipodystrophy phenotype that mirrors the human disease (Fig. 1).

It appears that NE connections can also influence gene activities in the nuclear interior as during lymphocyte activation we found that released genes that were flanked by unchanging NE-associated regions remained within <0.8 µm from the NE, presumably because the flanking contacts restrict their diffusion and thus promote their association in chromosome compartments in what we call the "constrained diffusion" hypothesis. We showed that several genes and an enhancer up to 14 Mb away from one another are all released upon lymphocyte activation and associate in A2 sub-compartments. This type of regulation could contribute temporal control to lymphocyte activation.

Other lines of investigation include: 

1) Nuclear size rectification as potential cancer therapy— Nuclear size changes in a tissue/cancer-type specific manner when cancer cells metastasize. Tissue-specific NETs also affect nuclear size in a cancer-type specific manner and we identified several drugs that reverse nuclear size changes in a cancer-type specific manner and also reduce cell migration and invasion. 

2) Virus-NET interactions— Investigating the recruitment of NETs by viruses to support virus functions for coronavirus replication centre formation and for herpesvirus nuclear egress. We are also mapping nuclear envelope influences on HIV-1 integration site selection.


figure showing the link between gene misregulation and human lipodystrophy

Figure legend

Genes misregulated in Ad-Tmem120a-/- mice are also misregulated in human lipodystrophy patients. 

a–d Quantification of genetic loci distance from NE shown as Tukey box plot representing median, cross on the box represents mean, bounds of box represents interquartile of the data, whiskers representing minima/maxima excluding outliers and dots represents outliers of more than 2/3 times of upper quartile. n = 105 loci per condition/gene/participant, P values were calculated by unpaired two-sided, Student’s t test and representative images of FISH for TRIM55, MYH1/MYH2, ANO5, and MYO18b gene loci in human primary SVF cells before and after induction of adipogenesis, scale bars: 5 μm: CTRL, healthy donor; pre, preadipocytes; adip, adipocytes; P1 and P2 stands for patient 1 and patient 2 respectively. Cells are from anonymised FPLD patients donating tissue. 

e Model of genome organisation role in adipogenesis and lipodystrophy. In preadipocytes, some muscle genes (e.g., Myh1) are in the nuclear interior that need to be strongly shut off in adipocytes and so are recruited to the NE when Tmem120a is expressed during adipogenesis. In the opposite direction, some genes are released from the NE and become activated when Tmem120a is expressed; however, in the absence of Tmem120a they remain at the NE and their expression is reduced compared to wild-type adipocytes. Enhancers and miRNA-encoding loci are similarly under Tmem120a positional and expression regulation. Ad-Tmem120a−/− adipocytes parallel human FPLD2 patients in that the normal repositioning of several genes that takes place during adipogenesis is disrupted with a concomitant change in expression. 

Figure from Czapiewski, R., Batrakou, D. G., de las Heras, J. I., Carter, R. N., Sivakumar, A., Sliwinska, M., Dixon, C. R., Webb, S., Lattanzi, G., Morton, N. M., and Schirmer, E. C.  (2022) Genomic loci mispositioning in Tmem120a knockout mice yields latent lipodystrophy. Nat. Commun.  13(1), 321.doi:10.1038/s41467-021-27869-2. PMID:35027552

Ward, A. I., de las Heras, J. I., Schirmer, E. C., and Fassati, A.  (2025) Memory CD4+ T cells sequentially restructure their 3D genome during stepwise activation. Front. Cell Dev. Biol. 13: 1514627. PMID:40018706

de las Heras, J. I., Todorow, V., Krečinić-Balić, L., Hintze, S., Czapiewski, R., Webb, S., Schoser, B., Meinke, P., and Schirmer, E. C. (2023) Metabolic, fibrotic, and splicing pathways are all altered in Emery-Dreifuss muscular dystrophy spectrum patients to differing degrees. Hum. Mol. Genet. 25:ddac264. PMID:36282542

Tollis, S., Rizzotto, A., Pham, N. T., Koivukoski, S., Sivakumar, A., Shave, S., Wildenhain, J., Zuleger, N., Keys, J. T., Culley, J., Zheng, Y., Lammerding, J., Carragher, N. O., Brunton, V. G., Latonen, L., Auer, M., Tyers, M., and Schirmer, E. C.  (2022) Chemical interrogation of nuclear size identifies compounds with cancer cell line-specific effects on migration and invasion. ACS Chem. Biol. doi:10.1021/acschembio.2c00004. PMID:35199530

Dixon, C. R., Malik, P., de las Heras, J. I., Saiz-Ros, N., de Lima Alves, F., Tingey, M., Gaunt, E., Richardson, A. C., Kelly, D. A., Goldberg, M. W., Towers, G. J., Yang, W., Rappsilber, J., Digard, P., and Schirmer, E. C.  (2021) STING nuclear partners contribute to innate immune signaling responses. iScience 24(9), 103055. PMID:34541469


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