Multiple sclerosis (MS) is characterized by neuroinflammation and demyelination of the central nervous system (CNS), leading to disablility. Genetic variants that confer MS risk implicate genes involved in immune function, while variants related to severity of the disease are associated with genes preferentially expressed within the CNS. Current MS therapies decrease relapse rates by preventing immune-mediated damage of myelin, but they ultimately fail to slow long-term disease progression, which apparently depends on CNS intrinsic processes. The molecular events that trigger progressive MS are still unknown. Here we report that the C-terminal region of TAF1 (the scaffolding subunit of the general transcription factor TFIID) is underrepresented in postmortem brain tissue from individuals with MS. Furthermore, we demonstrate in vivo, in genetically modified mice, that C-terminal alteration of TAF1 suffices to induce an RNA polymerase II (RNAPII)-elongation deficit that particularly affects oligodendroglial myelination-related genes and results in an MS-like brain transcriptomic signature, including increased expression of proinflammatory genes. This transcriptional profile is accompanied by CNS-resident inflammation, robust demyelination and MS-like motor phenotypes. We also identify numerous interactors of C-terminal TAF1 that participate in RNAPII-promoter escape, of which two show evidence for genetic association to MS. Our study reveals that TAF1 dysfunction converges with genetic susceptibility to cause transcriptional dysregulation in CNS cell types, such as oligodendrocytes, to ultimately trigger MS.

TAF1-dependent transcriptional dysregulation underlies multiple sclerosis