microRNAs are expressed with high spatio-temporal specificity during development. Understanding how these expression patterns are established is necessary to place miRNAs in the relevant cellular context and fully understand their function. The miRNA
lsy-6 is required for the functional left/right asymmetry between the two otherwise symmetric ASE sensory neurons. In the right ASE neuron (ASER) a transcription factor,
cog-1, results in a right-specific gene battery that includes a set of guanylate cyclase receptors (gcy).
lsy-6 functions in the left ASE (ASEL) to repress
cog-1 and trigger the left-specific fate, which relies on a distinct subset of gcy genes. The asymmetric function of
lsy-6 is supported by transcription of the miRNA only in ASEL. How asymmetric transcription of
lsy-6 is achieved and thus how ASE asymmetry is established during development was unknown. Here we show that the exclusive expression of
lsy-6 in ASEL results from two activation inputs on two separate enhancers flanking the
lsy-6 locus. These two inputs act in a temporally separated combinatorial manner, which we term "prime and boost". The
lsy-6 locus is primed by a transient input resulting in chromatin decompaction in the precursor of ASEL but not of ASER, 6 cell divisions before the ASEs are born. This early input is mediated by two transcription factors, TBX-37/38, which are transiently and asymmetrically expressed in the lineage that gives rise to ASEL but not ASER, at the AB16 stage - shortly after the lineages that give rise to ASEL and ASER diverge. TBX-37/38-mediated priming maintains the
lsy-6 locus competent for boosting of expression in ASEL 5 cell divisions later by CHE-1, a transcription factor that is bilaterally expressed in both ASEs. Absence of priming by TBX-37/38 in the ASER lineage results in
lsy-6 becoming refractory to further activation despite the presence of CHE-1 in ASER. This represents a novel transcriptional strategy for cell-type specific gene expression in development. In addition, because asymmetric TBX-37/38 expression is directly linked to the first embryonic Notch signal, we provide a mechanism linking one of the earliest embryonic asymmetries to the lateralized function of postmitotic neurons.