Repressive histone methylation regulates cardiac myocyte cell cycle exit

Area of Science:

• Epigenetics
• Cardiovascular Biology
• Cell Biology

Background:

• Mammalian cardiac myocytes (CMs) exit the cell cycle postnatally, limiting heart regeneration.
• The epigenetic mechanisms controlling CM cell cycle exit remain largely unknown.
• Histone H3 lysine 9 trimethylation (H3K9me3) is a repressive epigenetic mark.

Purpose of the Study:

• To investigate the role of H3K9me3 in silencing cell cycle genes in adult CMs (ACMs).
• To determine if H3K9me3 is essential for CM cell cycle exit and terminal differentiation.
• To assess the potential of H3K9me3 depletion for promoting cardiac regeneration.

Main Methods:

• Developed a transgenic mouse model overexpressing KDM4D to specifically remove H3K9me3 in CMs.
• Analyzed H3K9me3 levels at cell cycle gene promoters using ChIP-seq.
• Assessed CM proliferation, cell cycle gene expression, and heart growth in KDM4D-expressing mice.

Main Results:

• Loss of H3K9me3 in CMs preferentially disrupted cell cycle gene silencing, leading to increased gene expression.
• Overexpression of KDM4D induced CM cycling and hyperplasia, significantly increasing heart mass.
• H3K9me3 depletion prevented and reversed cell cycle exit in adult CMs, promoting hyperplastic growth.

Conclusions:

• H3K9me3 is a critical epigenetic regulator required for CM cell cycle exit and terminal differentiation.
• Targeting H3K9me3 in adult hearts can reactivate CM proliferation and promote cardiac regeneration.
• This study reveals a novel epigenetic mechanism controlling cardiac regenerative potential.