Genomic loci mispositioning in Tmem120a knockout mice yields latent lipodystrophy

Rafal Czapiewski, Dzmitry G. Batrakou, Jose I. las Heras, Roderick N. Carter, Aishwarya Sivakumar, Magdalena Sliwinska, Charles R. Dixon, Shaun Webb, Giovanna Lattanzi, Nicholas M. Morton and Eric C. Schirmer ()
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Rafal Czapiewski: University of Edinburgh
Dzmitry G. Batrakou: University of Edinburgh
Jose I. las Heras: University of Edinburgh
Roderick N. Carter: Queen’s Medical Research Institute, University of Edinburgh
Aishwarya Sivakumar: University of Edinburgh
Magdalena Sliwinska: University of Edinburgh
Charles R. Dixon: University of Edinburgh
Shaun Webb: University of Edinburgh
Giovanna Lattanzi: Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, Unit of Bologna
Nicholas M. Morton: Queen’s Medical Research Institute, University of Edinburgh
Eric C. Schirmer: University of Edinburgh

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Little is known about how the observed fat-specific pattern of 3D-spatial genome organisation is established. Here we report that adipocyte-specific knockout of the gene encoding nuclear envelope transmembrane protein Tmem120a disrupts fat genome organisation, thus causing a lipodystrophy syndrome. Tmem120a deficiency broadly suppresses lipid metabolism pathway gene expression and induces myogenic gene expression by repositioning genes, enhancers and miRNA-encoding loci between the nuclear periphery and interior. Tmem120a−/− mice, particularly females, exhibit a lipodystrophy syndrome similar to human familial partial lipodystrophy FPLD2, with profound insulin resistance and metabolic defects that manifest upon exposure to an obesogenic diet. Interestingly, similar genome organisation defects occurred in cells from FPLD2 patients that harbour nuclear envelope protein encoding LMNA mutations. Our data indicate TMEM120A genome organisation functions affect many adipose functions and its loss may yield adiposity spectrum disorders, including a miRNA-based mechanism that could explain muscle hypertrophy in human lipodystrophy.

Date: 2022
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DOI: 10.1038/s41467-021-27869-2

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