Multiple repeat regions within mouse DUX recruit chromatin regulators to facilitate an embryonic gene expression program

Abstract

The embryonic transcription factor DUX regulates chromatin opening and gene expression in totipotent cleavage-stage mouse embryos, and its expression in embryonic stem cells promotes their conversion to 2-cell embryo-like cells (2CLCs) with extraembryonic potential. However, little is known regarding which domains within mouse DUX interact with particular chromatin and transcription regulators. Here, we reveal that the C-terminus of mouse DUX contains five uncharacterized ~100 amino acid (aa) repeats followed by an acidic 14 amino acid tail. Unexpectedly, structure-function approaches classify two repeats as ‘active’ and three as ‘inactive’ in cleavage/2CLC transcription program enhancement, with differences narrowed to a key 6 amino acid section. Our proximity dependent biotin ligation (BioID) approach identified factors selectively associated with active DUX repeat derivatives (including the 14aa ‘tail’), including transcription and chromatin factors such as SWI/SNF (BAF) complex, as well as nucleolar factors that have been previously implicated in regulating theDuxlocus. Finally, our mechanistic studies reveal cooperativity between DUX active repeats and the acidic tail in cofactor recruitment, DUX target opening, and transcription. Taken together, we provide several new insights into DUX structure-function, and mechanisms of chromatin and gene regulation.

Dux activates metabolism-lactylation-MET network during early iPSC reprogramming with Brg1 as the histone lactylation reader

“…Our RNA-seq analysis further demonstrated a significant upregulation of Klf4 expression upon Dux overexpression during reprogramming. Additionally, CUT&tag data from ESC indicated enrichment of Dux in the distal region of Klf4, suggesting a potential regulatory relationship between the two factors ( 51 ) (data not shown). Our research sheds light on the role of Dux in augmenting the efficiency of iPSCs reprogramming induced by the classic Yamanaka factors.…”

Species-Specific Transcription Factors Associated with Long Terminal Repeat Promoters of Endogenous Retroviruses: A Comprehensive Review

“…Zscan4c binds to the GLTSCR1/like-containing BAF complex (GBAF), a chromatin remodeling complex, via its SCAN domains to efficiently initiate MT2 functions, as determined by ChIP analysis [ 216 ]. On the other hand, MERV-L LTR is activated by DUX in the 2C-embryo-like cells [ 140 , 141 , 217 , 218 , 219 ]. In addition, p53 is required for the DUX expression in FSHD cells [ 220 ].…”