Nup93 and CTCF co-modulate spatiotemporal dynamics and function of the HOXA gene cluster during differentiation

Abstract

The nuclear pore complex (NPC) regulates nuclear transport of RNA and proteins. Also, nucleoporins regulate chromatin organization and gene expression. However, the role of nucleoporins in the temporal regulation of gene expression during differentiation is unclear.Here we investigated the role of nucleoporin Nup93, in regulating HOXA gene expression during differentiation. ChIP-Seq analysis revealed that Nup93 associates with genes involved in development and differentiation such as HOXA. Furthermore, Nup93 occupancy overlaps with the chromatin organizer -CTCF, suggesting a co-regulatory role of Nup93 and CTCF in HOXA gene regulation. Interestingly, Nup93 and CTCF showed antagonistic roles in regulating expression levels of genes at the 3' and 5' end of the HOXA gene cluster in undifferentiated cells. Furthermore, HOXA gene locus untethered from the nuclear periphery upon Nup93 but not CTCF depletion, consistent with its upregulation. In addition, occupancy of Nup93 and CTCF on HOXA gene locus progressively declined during differentiation but was re-enriched on HOXA on Day 21 of differentiation consistent with its re-repression. Remarkably, the HOXA gene locus relocates toward the nuclear periphery upon differentiation. In summary, this study reveals that Nup93 is a key modulator of the spatiotemporal dynamics and function of the HOXA gene locus during differentiation.

High-precision mapping of nuclear pore-chromatin interactions reveals new principles of genome organization at the nuclear envelope

“…Together, these results strengthen the possibility of NPCs mediating the organization of SEs at the periphery through interactions with chromatin structural proteins. These results also corroborate recent studies showing the interaction of Nups like Nup153 or Nup93 with CTCF and cohesin (Kadota et al, 2020;Labade et al, 2019;Sachani et al, 2018). The knockdown of Nup153 influences the genome-wide binding of CTCF and cohesin (Kadota et al, 2020).…”