RT Journal Article
SR Electronic
T1 POGZ suppresses 2C transcriptional program and retrotransposable elements
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.02.514968
DO 10.1101/2022.11.02.514968
A1 Sun, XY
A1 Zhang, TZ
A1 Cheng, LX
A1 Jiang, W
A1 Sun, YH
YR 2022
UL http://biorxiv.org/content/early/2022/11/03/2022.11.02.514968.abstract
AB The POGZ gene has been found frequently mutated in neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and intellectual disability (ID). We have recently shown that POGZ maintains mouse embryonic stem cells (ESCs) as a chromatin regulator and a transcription factor. However, the exact mechanisms remain unclear. Here we show that POGZ plays important role in the maintenance of ESCs by silencing the Dux gene and certain endogenous retroviruses (ERVs). POGZ directly binds to the Dux gene and ERVs, and its depletion leads to up-regulation of 2C genes and the repetitive elements such as RLTR9E and IAP (the intracisternal A-type particles), resulting in transition to a 2C-like (2CLC) state and genome instability. POGZ regulates ESC heterochromatin state by association and recruiting TRIM28 and SETDB1, and its loss leads to increased H3K4me3 and H3K27ac, and decreased H3K9me3 at local chromatin. Activation of POGZ-bound ERVs is associated with up-regulation of nearby neural genes. Chimeric transcripts that are initiated within ERVs and spliced to genic exons are highly expressed in Pogz−/− ESCs. Our findings establish that POGZ is required for the maintenance of ESCs by repressing Dux and silencing ERVs, which may provide important insights into the disease pathology caused by POGZ dysfunction.HighlightsPOGZ depletion leads to activation of 2C genesPOGZ depletion leads to deregulation of ERVsPOGZ directly binds and represses DuxPOGZ associates with TRIM28/SETDB1 to maintain heterochromatin state to silence ERVsActivation of POGZ-bound ERVs is associated with up-regulation of nearby neural genesCompeting Interest StatementThe authors have declared no competing interest.