Targeted Enhancer Activation by a Subunit of the Integrator Complex

The control of cell fate is an epigenetic process initiated by transcription factors (TFs) that recognize DNA motifs and recruit activator complexes and transcriptional machineries to chromatin. Lineage specificity is thought to be provided solely by TF-motif pairing, while the recruited activators are passive. Here, we show that INTS13, a subunit of the Integrator complex, operates as monocytic/macrophagic differentiation factor. Integrator is a general activator of transcription at coding genes and is required for eRNA maturation. Here, we show that INTS13 functions as an independent sub-module and targets enhancers through Early Growth Response (EGR1/2) TFs and their co-factor NAB2. INTS13 binds poised monocytic enhancers eliciting chromatin looping and activation. Independent depletion of INTS13, EGR1, or NAB2 impairs monocytic differentiation of cell lines and primary human progenitors. Our data demonstrate that Integrator is not functionally homogeneous and has TF-specific regulatory potential, revealing a new enhancer regulatory axis that controls myeloid differentiation. Barbieri et al. demonstrate that a subunit of the Integrator complex, INTS13, is required for monocytic commitment of myeloid progenitors. INTS13 is a modular component of Integrator recruited to poised enhancers via the EGR1 transcription factor and its co-factor NAB2. The INTS13/EGR1/NAB2 axis is essential to elicit enhancer-mediated gene activation.