October 31, 2020

mTOR inhibition in primary neurons and the developing brain represses transcription of cholesterol biosynthesis genes and alters cholesterol levels

Dysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders to monogenic syndromes as for example Tuberous sclerosis complex. Thus, maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy and metabolism. On a molecular level, however, the consequences of mTOR activation are not well understood, especially in the brain. Thus, while it was shown that in cells outside the central nervous system mTORC1 activity is necessary for activating gene transcription of different metabolic pathways this mechanism is ill defined in the brain. By combining mTORC1 inhibition with RNA-sequencing we identified numerous genes of the sterol/cholesterol biosynthesis pathway to be downstream targets of mTORC1 in vitro in primary neurons and in vivo in the developing cerebral cortex of the mouse. Of note, reduced expression of these genes upon mTORC1 inhibition translated into reduced cholesterol levels. We further show that while mTORC1 does not regulate chromatin accessibility or RNA stability of these genes it drives transcription of their DNA. Using a bioinformatics approach, we identified binding sites for the transcription factors SREBP, SP1 and NF-Y to be enriched in the promoters of mTORC1 target genes and confirmed binding of NF-YA by ChIP-qPCR. Altogether, our results indicate that mTORC1 is an important regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important contributing factor in the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling.

 bioRxiv Subject Collection: Neuroscience

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