Böttger, ThomasHachim, SalmaSalmaHachim2025-06-242025-06-242024https://jlupub.ub.uni-giessen.de/handle/jlupub/20637https://doi.org/10.22029/jlupub-19987INO80 is an evolutionary conserved chromatin remodelling complex composed of over 15 different subunits organized in structural modules. The INO80 complex acquires different subunits, including the transcription factor YY1, contingent on the tissue specific function the complex may carry out. INO80 alters DNA accessibility of chromatin in an ATP-dependent manner through histone variant exchange, nucleosome spacing, nucleosome sliding and nucleosome eviction. These INO80 dependent processes contribute to various fundamental nuclear DNA based functions classified through transcriptional regulation, DNA replication as well as DNA damage repair at double strand breaks. INO80 has been shown to be essential for embryonic development and to play a role in several cell types. Germline deletion of Ino80 leads to early embryonic lethality due to failure in gastrulation, growth retardation, and significant cell death as a consequence of the loss of INO80-dependent transcriptional regulation. In addition to this, INO80-dependent transcriptional regulation has been shown to control cell cycle in cardiac endothelial cells as well as proliferation in hepatocytes, satellite cells and cardiac endothelial cells. Nonetheless, the functions of INO80 on a molecular level and its contribution in the development, contractility and regeneration of smooth muscle cells in the cardiovascular system are yet to be understood. To characterize the functions of INO80 in vascular smooth muscle cells (VSMCs), the Ino80-encoding gene was inactivated in smooth muscle cells of mice using the CreloxP system. This work demonstrates for the first time how two essential functions of the INO80 chromatin remodelling complex contribute to different aspects of the INO80 loss of function phenotype in VSMCs. Global analysis of the function of INO80 in VSMCs transcriptional regulation revealed that loss of INO80 led to major changes in transcriptional programs and that YY1 is an essential co-factor of INO80 transcriptional regulation. We report that INO80 binds to the myocardin promoter to transcriptionally activate myocardin and thereby maintains VSMCs contractility most likely through recruitment by YY1. Loss of this function leads to a decrease in VSMCs contractility, altered migration, as well as blunted or unsuited responsiveness to environmental cues. Moreover, we show that the DNA repair function of INO80 controls VSMCs metabolism by regulating FOXO1 activity through a cascade of defined regulatory events involving an increase in DNA damage induced ROS production. Finally, we propose that changes in the VSMCs phenotype upon loss of INO80 culminate in the acceleration of atherosclerosis development as reported in humans upon homozygous missense mutation of Ino80d, a subunit of the INO80 complex. In summary, this study demonstrates how two distinct molecular functions of a chromatin remodeler affect VSMCs physiological performance and progression of atherosclerosis.enAttribution-NonCommercial-NoDerivatives 4.0 Internationalddc:570