The impact of cell geometry and the cytoskeleton on the nucleo-cytoplasmic localisation of the SMYD3 methyltransferase suggests that the epigenetic machinery is mechanosensitive

Abstract

Mechanical cues from the cellular microenvironment are converted into biochemical signals controlling diverse cell behaviours, including growth and differentiation. But it is still unclear how mechanotransduction ultimately affects nuclear readouts, genome function and transcriptional programs. Key signaling pathways and transcription factors can be activated, and can relocalize to the nucleus, upon mechanosensing. Here, we tested the hypothesis that epigenetic regulators, such as methyltransferase enzymes, might also contribute to mechanotransduction. We found that the SMYD3 lysine methyltransferase is spatially redistributed dependent on cell geometry (cell shape and aspect ratio) in murine myoblasts. Specifically, elongated rectangles were less permissive than square shapes to SMYD3 nuclear accumulation, via reduced nuclear import. Notably, SMYD3 has both nuclear and cytoplasmic substrates. The distribution of SMYD3 in response to cell geometry correlated with cytoplasmic and nuclear lysine tri-methylation (Kme3) levels, but not Kme2. Moreover, drugs targeting cytoskeletal acto-myosin induced nuclear accumulation of Smyd3. We also observed that square vs rectangular geometry impacted the nuclear-cytoplasmic relocalisation of several mechano-sensitive proteins, notably YAP/TAZ proteins and the SETDB1 methyltransferase. Thus, mechanical cues from cellular geometric shapes are transduced by a combination of transcription factors and epigenetic regulators shuttling between the cell nucleus and cytoplasm.

Osteosarcoma mechanobiology and therapeutic targets

“…Some of the models include cancer cells grown on in vitro crosshatched fibres, which induce metabolic upregulation and transcriptional changes in genes related to metabolism and post‐transcriptional modification (Jana et al, 2019 ). Additionally, cells grown on printed PDMS stamps of different shapes can alter nuclear import of methyltransferases such as tose encoded by SETDB1 and SMYD3 due to change in cell shape and integrity of actin filaments (Pereira et al, 2020 ).…”

Cell shape: effects on gene expression and signaling

“…The link between mechanotransduction and epigenetic regulators was the focus of very recent studies published in 2019 and 2020 (Alisafaei et al 2019;Dreger et al 2019;Ferrari and Pesce 2019;Mathur et al 2020). Pereira et al (2020) reported that the nuclear and cytoplasmic localization of SMYD3 lysine methyltransferase, an epigenetic modulator, was governed by cell shape and AR in murine myoblasts. Moreover, the authors stated that the transcriptional coactivator with PDZ-binding motif (TAZ) transcription factor, which is an important effector of mechanotransduction pathways (Dupont 2016;Dupont et al 2011), was regulated by the size of the cell and the AR.…”