NCOA1, NCOA2 and NCOA3 identified as histone succinyltransferases in mammalian cell studies
Authors report that three nuclear receptor coactivators catalyze bulk histone succinylation, and that this mark helps the Mediator complex bind promoters in cell experiments.
Researchers report that the nuclear receptor coactivators NCOA1, NCOA2 and NCOA3 act as histone succinyltransferases (HSTs) and are responsible for bulk histone succinylation in mammalian cells, according to a paper available via doi.org nature.com
doi.orgnature.comOpen source ↗. Histone succinylation is a conserved lysine acylation, but its mechanism and its role in transcription had remained unclear. The work combines in vitro assays with genome-wide profiling in cancer cells and embryonic stem cells.
NCOA proteins as succinyltransferases
Classic acetyltransferases such as CBP/p300 possess several acyltransferase activities. NCOA1/2/3, by contrast, exhibit only HST activity. The authors report that the proteins drive the formation of phase-separation condensates through this activity.
In mouse embryonic stem cells lacking Ncoa1 and Ncoa2, rapid targeted degradation of NCOA3 caused a marked, immediate loss of bulk histone succinylation. It was accompanied by a widespread decline in global transcriptional activity.
Mediator as a reader of the mark
In vitro binding assays identified the Mediator complex as a specific reader of succinylated histone tail peptides and nucleosomes nature.com
doi.orgnature.comOpen source ↗. Epigenome profiling, based on ChIP-seq, CUT&Tag-seq, RNA-seq and TT-seq data, showed that histone succinylation catalyzed by NCOA1/2/3 is highly enriched at gene promoters. According to the authors, this mark is essential for the association of the Mediator complex with promoters.
The NCOA family of HSTs is also critically important for global transcriptional activity in both cancer cells and embryonic stem cells. The authors conclude that NCOA1/2/3 are unique histone succinyltransferases and that histone succinylation is a critical regulator of Mediator promoter association and of global transcriptional activation.
The results were obtained in vitro and in cultured mammalian cells. The material contains no data on animals or patients.
