Abstract
Recent studies have shown that a subset of nucleoporins (Nups) can detach from the nuclear pore complex and move into the nuclear interior to regulate transcription. One such dynamic Nup, called Nup98, has been implicated in gene activation in healthy cells and has been shown to drive leukemogenesis when mutated in patients with acute myeloid leukemia (AML). Here we show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82-Set1A/COMPASS (complex of proteins associated with Set1) complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark. Depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and subsequently ablates H3K4me3 at adjacent promoters. Furthermore, expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at abnormal regions and up-regulation of associated genes. Our findings establish a function of Nup98 in hematopoietic gene activation and provide mechanistic insight into which Nup98 leukemic fusion proteins promote AML.
Highlights
The nuclear pore complex (NPC) is an ∼125-mDa protein assembly that spans the nuclear envelope (NE) to regulate transport of macromolecules to and from the nucleus of the cell (Wente and Rout 2010; Hoelz et al 2011; Solmaz et al 2011; Raices and D’Angelo 2012; Hurt and Beck 2015)
As a first step to understand the role of Nup98 in intranuclear gene regulation in H3K4me3 poietic progenitor cells (HPCs), we wanted to observe how Nup98 interacts with chromatin
We found that most Nup98 chromatin immunoprecipitation (ChIP) peaks align with gene promoters adjacent to areas of H3K4me3 (Fig. 1A,B; Supplemental Fig. S1A)
Summary
The nuclear pore complex (NPC) is an ∼125-mDa protein assembly that spans the nuclear envelope (NE) to regulate transport of macromolecules to and from the nucleus of the cell (Wente and Rout 2010; Hoelz et al 2011; Solmaz et al 2011; Raices and D’Angelo 2012; Hurt and Beck 2015). Nup regulates H3K4me poietic progenitor cells (HPCs) and down-regulated upon differentiation, become chronically active, resulting in the inhibition of cell differentiation and the promotion of self-renewal (Wang et al 2007) This model is challenged by the fact that multiple Nup translocations lack DNA-binding domains and probably cannot directly disrupt gene expression at aberrant DNA-binding sites (Franks and Hetzer 2013). Another study found that the transport factor Crm, which was shown previously to interact with Nup, recruits the Nup98-HOXA9 translocation to the HOX locus to disrupt gene expression and promote AML (Oka et al 2016) These findings suggest that the common N-terminal domain and not the C-terminal fusion partner of Nup fusion proteins is critical for chromatin recruitment and offers a unifying model for how Nup fusions with very different C-terminal translocation partners can trigger similar phenotypes. The important question of how recruitment of Nup or Nup fusion proteins triggers gene activation remains unanswered
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