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Significance The mTORC1 signaling pathway senses nutrient signals and controls cell growth partly by regulating mRNA translation. 5′ TOP motifs are defining features of mTORC1-regulated mRNAs, but their prevalence throughout the transcriptome and the mechanism that controls them are not fully understood. Here we show that the mTORC1 effector LARP1 is the master regulator of TOP mRNAs genome-wide. We discover features of TOP sequences that tune their regulatory potential across a continuous spectrum and define a metric called a TOPscore that quantifies them. Analysis of TOPscores across the transcriptomes of 16 mammalian tissues defines both constitutive TOP mRNAs and tissue-specific variants resulting from alternative transcription initiation. These results establish global principles of a dynamic and tunable program of nutrient-regulated gene expression.

Global analysis of LARP1 translation targets reveals tunable and dynamic features of 5′ TOP motifs