In eukaryotes, a meter-long DNA, complexed with histone and non-histone proteins, is packed into higher order chromatin organization i.e., chromosomes, which are non-randomly organized within the nucleus of living cells. in addition, the nucleus of living cells is held under a prestressed state by the cytoskeletal filaments, that link the plasma membrane and the nuclear membrane. Recent studies have shown that the extracellular mechanical forces are transduced to the nucleus, via the cytoskeletal filaments and biochemical signaling, to alter the chromatin organization, inter-chromosome contacts and gene expression programs, although the underlying mechanisms are unclear. in this talk, I will highlight the tight coupling between cell mechanics, chromatin organization and gene expression. in addition, I will discuss how mechanically induced alterations in chromatin organization can regulate cell-fate decisions. Furthermore, I will show that spatial alterations in chromatin organization, identified using fluorescence imaging combined with machine learning, can serve as robust biomarkers for cell-fate decisions.