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Eric Schirmer


Avik Basu, Rafal Czapiewski, Alina Gukova, Jose de las Heras, Alexandr Makarov, Peter Meinke, Michael I. Robson, Natalia Saiz Ros, Andrea Rizzotto, Phu Le Thanh, Sylvain Tollis

Nuclear envelope transmembrane protein regulation of tissuespecific genome organisation in differentiation and disease

Eric gives a brief overview of his research.


The nuclear envelope (NE) is a double membrane system connecting on one side to cytoplasmic filaments and on the other to chromatin. Mutations in ubiquitous NE proteins cause many diseases with tissue-specific pathologies including muscular dystrophies, lipodystrophies, neuropathy, dermopathy, bone disorders and premature-aging syndromes. The field posited to yield pathology mutated NE proteins would likely disrupt cytoskeletal
mechanics, genome organisation and regulation, or the cell cycle; however, these functions still failed to explain the tissue-specificity of pathology. To explain how mutations in ubiquitous proteins can yield tissue-specific pathologies we postulated that tissue-specific partners mediate pathology and identified candidate partners with proteomics. Strikingly, we found that the majority of NE transmembrane proteins (NETs) are tissue-specific and screening these NETs has identified distinct sets with functions in cytoskeletal organisation, cell cycle progression, nuclear size regulation, differentiation and genome organization, perhaps explaining the NE-linked diseases.

The laboratory is principally focused on understanding the role of tissue-specific NETs in spatial genome organisation and its consequences for gene regulation. We have studied the role of these NETs in adipogenesis, myogenesis, liver and lymphocyte activation, finding for example that three muscle NETs that re-position genes during myogenesis together affect 38% of all genes that normally change during myogenesis and when combinatorially knocked down almost completely block myogenesis. The genes directly affected by these NETs for re-positioning tend to be needed early in differentiation, but then have to be tightly shut down because they become inhibitory for differentiation. Thus, NET recruitment of genes to the NE appears to be a mechanism for tighter regulatory control. Importantly, in a separate experimental approach we sequenced several unlinked patients with Emery- Dreifuss muscular dystrophy, which was already linked to the NE but had 53% of patients unlinked, and found mutations principally in the muscle NETs important for gene repositioning. This further argues the importance of this novel regulatory mechanism.

We also have several other lines of investigation going. We use a crosslinking-mass spectrometry approach in collaboration with the Rappsilber lab to study the structure of intermediate filament lamins and their partners. Nuclear size changes in a tissue-specific manner in several cancer types and we are screening for small molecule effectors of nuclear size regulation in collaboration with the Auer and Tyers labs. Finally, we are investigating the interaction of herpesviruses with the NE, predicting that NET interactions will be crucial to this poorly studied phase of the virus life cycle.

Selected publications:

Batrakou, D. G., de las Heras, J. I., Czapiewski, R., Mouras, R., and Schirmer, E. C. (2015) TMEM120A and B: Nuclear envelope transmembrane proteins important for adipocyte differentiation. PLoS One 10(5):e0127712.
Meinke, P., Schneiderat, P., Srsen, V., Korfali, N., Le Thanh, P., Cowan, G., Cavanagh, D. R., Wehnert, M., Schirmer, E. C., and Walter, M. C. (2015) Abnormal proliferation and spontaneous differentiation of myoblasts from a symptomatic female carrier of X-linked Emery-Dreifuss muscular dystrophy.
Neuromuscul. Disord. 25, 127-136.
Malik, P., Zuleger, N., de las Heras, J. I., Ros, N., Makarov, A. A., Lazou, V., Meinke, P., Waterfall, M., Kelly, D. A., and Schirmer, E. C. (2014) NET23/STING promotes chromatin compaction from the nuclear envelope. PLoS One 9(11), e111851.

A. Gene position and expression changes from muscle-specific NETs. Left panel, myoblast (MB) to myotube (MT) differentiation with gene re-positioning changes (I, interior; P, periphery) from DamID plotted against expression data. Right panel, mNET39 knockdown yielded less repression for genes that normally move to the periphery (IP), but also yielded less activation for some genes that move to the interior (PI). B. Gene re-positioning NETs function in differentiation. Single knockdowns (KDs) had minimal effects on differentiation, but double KD of fat-specific NETs blocks adipogenesis (white, fat) while triple KD of muscle NETs blocks myogenesis (red, differentiated). C. Crosslinking mass spectrometry on lamin A reveals the unstructured region just after the end of the coiled-coil rod folds back over the rod to form a “knot” that could explain the considerable stability of lamin dimers. Interestingly, several mutations linked to EDMD and dilated cardiomyopathy with conduction defect (DCM-CD) occur in this region.