Mesenchymal stem cells (MSCs) can be differentiated into osteoblasts, myoblasts, or adipocytes, depending upon the available cohort of regulatory proteins, providing an example of the developmental relevance of gene bookmarking. A ribosomal DNA (rDNA) repeat that is occupied by the proliferation-promoting Myc transcription factor is illustrated. Myc upregulates rRNA transcription in non-committed, proliferating MSCs and contributes to growth potential. In response to extracellular signals, MSCs express either Runx2 when differentiated into osteoblasts, muscle regulatory factors (i.e., MyoD and myogenin) when differentiated into myoblasts, or C/EBP upon adipocyte differentiation. These phenotypic proteins occupy rDNA repeats as cells differentiate into their respective lineages and down regulate rRNA expression, concomitant with the exit of MSCs from the cell cycle, reduced cell growth and initiation of a differentiation.