The stability of the myelinating oligodendrocyte transcriptome is regulated by the nuclear lamina. Cell Rep. 2023;42(8):112848.
Cell Rep. 2023;42(8):112848.
This work was performed thanks to grants from the National Institutes of Health (R35- NS111604) to P.C. and fellowships from the National Multiple Sclerosis Society to M.P. (FG-1907-34565) and J.P. (FG-1804-30631). This study was also sup- ported by the National Institutes of Health (NIH), Bethesda, MD, under award numbers R01MH125246, R01AG065582, R01AG067025, R01AG050986, U01MH116442, and R01MH109677. The NMDR metabolomics repository is supported by NIH grant U2C-DK119886 and an OT2-OD030544 grant.
Oligodendrocytes are specialized cells that insulate and support axons with their myelin membrane, allowing proper brain function. Here, we identify lamin A/C (LMNA/C) as essential for transcriptional and functional stability of myelinating oligodendrocytes. We show that LMNA/C levels increase with differentiation of progenitors and that loss of Lmna in differentiated oligodendrocytes profoundly alters their chromatin accessibility and transcriptional signature. Lmna deletion in myelinating glia is compatible with normal developmental myelination. However, altered chromatin accessibility is detected in fully differentiated oligodendrocytes together with increased expression of progenitor genes and decreased levels of lipid-related transcription factors and inner mitochondrial membrane transcripts. These changes are accompanied by altered brain metabolism, lower levels of myelin-related lipids, and altered mitochondrial structure in oligodendrocytes, thereby resulting in myelin thinning and the development of a progressively worsening motor phenotype. Overall, our data identify LMNA/C as essential for maintaining the transcriptional and functional stability of myelinating oligodendrocytes.