In eukaryotic cells gene regulation is dependent on global genome organization. This is achieved, in response to favorable environmental conditions, through spatial redistribution of chromatin and changes in global epigenetic levels. This eventually drives movement of gene-rich chromatin loops and formation of DNA loops, consolidating neighborhoods of gene expression and silencing. One of the challenges for future work is to examine how these neighborhoods are formed and whether they host genes involved in the same cellular functions for sustained expression or silencing over time. In the present review, we summarize evidence that actin and actin-associated proteins regulate gene activity. Furthermore we discuss how these specific nuclear tasks in which actin is engaged are important to organize and consolidate the mammalian genome, ensuring gene activation and repression of gene programs important to establish cellular identity. We propose that these mechanisms are essential to control cellular development and differentiation. (C) 2017 Elsevier Inc. All rights reserved.