Acidic transcription factors position the genome at nuclear speckles through transcription dependent and independent mechanisms
TL;DR
This work demonstrates establishment of genome-wide NS-association without active transcription and establishes diverse and partially redundant NS-targeting activities, which may facilitate dynamic gene positioning at NS periphery for context-specific transcriptional responses.
Abstract
SUMMARY A small fraction of the genome positions reproducibly near nuclear speckles (NS), increasing expression and/or splicing efficiency of NS-associated genes. How specific genomic regions in mammalian cells target to NS remains unclear. Here we demonstrate establishment of genome-wide NS-association without active transcription. We show that DNA sequences derived from NS-associated regions integrated as transgenes autonomously target to NS. By systematically dissecting one such genomic locus, the COL1A1-SGCA locus, we identified redundant NS-targeting cis-regulatory elements, including a ~600 bp fragment with 17 binding motifs for 8 transcription factors (TFs). Four NS-targeting TFs within this fragment contain acidic activation domains (AADs) that provide both chromatin-context and transcription-dependent NS-targeting, a property that appears common among several other tested AADs. A subset of acidic activator TFs contain an additional, transcription-independent NS-targeting activity. Our findings establish diverse and partially redundant NS-targeting activities, which may facilitate dynamic gene positioning at NS periphery for context-specific transcriptional responses.