What question did this study set out to answer?

This research aims to understand how cell density influences SETDB1's role in regulating YAP1-mediated transcription.

January 21, 2026FEBS Letters0 citationsOpen Access

Cell density–dependent nuclear‐cytoplasmic shuttling of SETDB 1 integrates with Hippo signaling to regulate YAP 1‐mediated transcription

JEJaemin EomKorea Research Institute of Bioscience and Biotechnology JJJ. S. JangTRIUMF JPJung Sun ParkKorea Research Institute of Bioscience and Biotechnology

Key Points

This research aims to understand how cell density influences SETDB1's role in regulating YAP1-mediated transcription.
Investigated SETDB1 subcellular localization under varying cell densities.
Examined effects of SETDB1 depletion on YAP1 phosphorylation and accumulation.
Conducted transcriptomic analysis of SETDB1 knockout cells.
Performed immunoprecipitation to explore SETDB1 interactions with TEAD1.
SETDB1 localizes differently based on cell density, with nuclear exclusion and degradation at high density.
Depletion of SETDB1 leads to reduced YAP1 phosphorylation and increased nuclear accumulation.
Transcriptomic analysis shows upregulation of target genes associated with YAP1-TEAD1.
SETDB1 was shown to compete with YAP1 for binding to TEAD1 at gene promoters.

Abstract

SETDB1, a H3K9 methyltransferase involved in nuclear transcriptional silencing, also localizes to the cytoplasm through unclear mechanisms. Here, we identify cell density as key regulator of SETDB1 subcellular localization and demonstrate its role in modulating the Hippo signaling pathway. Under low‐density culture, SETDB1 distributes between nucleus and cytoplasm, whereas high‐density culture triggers nuclear exclusion and proteasomal degradation. SETDB1 depletion reduces YAP1 phosphorylation and increases nuclear YAP1 accumulation. Transcriptomic analysis of SETDB1 knockout cells revealed upregulation of YAP1–TEAD1 target genes (YTGs). Immunoprecipitation experiments showed that SETDB1 is recruited to YTG promoters via TEAD1 and competes with YAP1 for TEAD1 binding. These findings reveal that SETDB1 regulates Hippo pathway output through YAP1 phosphorylation modulation and competitive transcriptional repression.

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