ZFP560 facilitates KAP1-dependent chromatin repression to regulate exit from totipotency

Qingsheng Han; Lichao Wang; Chang Liu; Huaxin Yu; Hao Zhou; Min Wei; Zongjin Li; Na Liu

doi:10.1016/j.jgg.2026.04.022

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ZFP560 facilitates KAP1-dependent chromatin repression to regulate exit from totipotency

doi: 10.1016/j.jgg.2026.04.022

a. School of Medicine, Nankai University, Tianjin 300071, China;
b. College of Life Sciences, Nankai University, Tianjin 300071, China

Funds:

D Plan (2021YFA1101002), and Tianjin Natural Science Foundation (22JCYBJC01220).

This work was supported by grants from the National Natural Science Foundation of China (32371217, 32070860), National Key R&

Received Date: 2026-01-10
Accepted Date: 2026-04-29
Rev Recd Date: 2026-04-27

Available Online: 2026-05-07

Abstract

Abstract

KRAB zinc finger proteins (KRAB-ZFPs) are the most abundant transcriptional regulators and epigenetic repressors in mammals and contribute to the silencing of transposable elements (TEs) during embryonic development. However, the early effectors of the KRAB-ZFP family during embryonic development and cell state transition remain largely unexplored. Here, we identify that zinc finger protein 560 (ZFP560) is involved in the regulation of early embryonic development and the transition from totipotency in mice. ZFP560 safeguards heterochromatin structure by recruiting KAP1 to facilitate the exit of totipotency. The deficiency of ZFP560 disrupted heterochromatin formation, significantly halting the transition from totipotency to pluripotency. Similarly, the overexpression of ZFP560 promotes exit from the MERVL-positive state and suppresses expression of 2-cell (2C) transcription factors by recruiting KAP1 via its KRAB domain, thereby reducing chromatin accessibility. Taken together, these findings reveal that ZFP560 is a highly expressed 2C-specific KRAB-ZFP transcription factor and a mediator that facilitates the exit from totipotency, providing insights into the epigenetic regulation of early embryonic development.
- Embryonic stem cell,
- Pluripotency,
- Totipotency,
- 2-cell-like cells,
- KRAB-ZFPs,
- KAP1

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