β-Actin-dependent global chromatin organization and gene expression programs control cellular identity.
Xie X1, Almuzzaini B2, Drou N3, Kremb S3, Yousif A3, Farrants AÖ4, Gunsalus K1,3,5, Percipalle P1,4.
1 Biology Program, New York University Abu Dhabi (NYUAD), Abu Dhabi, United Arab Emirates.
2 Medical Genomic Research Department, King Abdullah International Medical Research Center/King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia.
3 NYUAD Center for Genomics and Systems Biology, Abu Dhabi, United Arab Emirates.
4 Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; and.
5 Department of Biology, Center for Genomics and Systems Biology, New York University, New York, New York, USA.
Year of Publication:
During differentiation and development, cell fate and identity are established by waves of genetic reprogramming. Although the mechanisms are largely unknown, during these events, dynamic chromatin reorganization is likely to ensure that multiple genes involved in the same cellular functions are coregulated, depending on the nuclear environment. In this study, using high-content screening of embryonic fibroblasts from a β-actin knockout (KO) mouse, we found major chromatin rearrangements and changes in histone modifications, such as methylated histone (H)3-lysine-(K)9. Genome-wide H3K9 trimethylation-(Me)3 landscape changes correlate with gene up- and down-regulation in β-actin KO cells. Mechanistically, we found loss of chromatin association by the Brahma-related gene ( Brg)/Brahma-associated factor (BAF) chromatin remodeling complex subunit Brg1 in the absence of β-actin. This actin-dependent chromatin reorganization was concomitant with the up-regulation of sets of genes involved in angiogenesis, cytoskeletal organization, and myofibroblast features in β-actin KO cells. Some of these genes and phenotypes were gained in a β-actin dose-dependent manner. Moreover, reintroducing a nuclear localization signal-containing β-actin in the knockout cells affected nuclear features and gene expression. Our results suggest that, by affecting the genome-wide organization of heterochromatin through the chromatin-binding activity of the BAF complex, β-actin plays an essential role in the determination of gene expression programs and cellular identity.-Xie, X., Almuzzaini, B., Drou, N., Kremb, S., Yousif, A., Östlund Farrants, A.-K., Gunsalus, K., Percipalle, P. β-Actin-dependent global chromatin organization and gene expression programs control cellular identity.