Nuclear compression-mediated DNA damage drives ATR-dependent Lamin expression and mouse ESC differentiation

Area of Science:

• Cell Biology
• Biophysics
• Developmental Biology

Background:

• Embryonic stem cells (ESCs) possess a DNA damage response (DDR) crucial for survival.
• The impact of physical forces on DNA damage and ESC fate is not well understood.

Purpose of the Study:

• To investigate how substrate stiffness influences DNA damage and differentiation in mouse ESCs (mESCs).
• To elucidate the role of the ATR/CHK1 DDR pathway in stiffness-mediated mESC differentiation.

Main Methods:

• Utilized varying substrate stiffness to induce differential spreading and nuclear compression in mESCs.
• Assessed DNA damage, DDR factor activation (ATR, CHK1), and Lamin A/C expression.
• Employed ATR and CHK1 inhibitors to determine their role in differentiation.

Main Results:

• Substrate stiffness induced DNA damage in mESCs via nuclear compression, leading to differentiation.
• Differentiation correlated with DNA damage and activation of ATR and CHK1.
• Inhibition of ATR or CHK1 reduced Lamin A/C expression, suggesting pathway involvement.

Conclusions:

• mESC differentiation is driven by nuclear compression-induced DNA damage.
• The ATR-dependent pathway plays a key role in modulating Lamin A/C during stiffness-mediated differentiation.