Chromatin organization within the nucleus is not only important for normal cellular function but has also been demonstrated to play a role in the maintenance of cellular identity. Activation of the right genes at the right time is crucial for proper development, yet there is still much to uncover regarding how genes within repressed heterochromatin are accessed for transcription. The histone modification H3K9me2 is found on regions of chromatin that display a largely peripheral localization in the nucleus, an environment that is transcriptionally repressed. While it has been demonstrated that the movement of genomic loci from the nuclear periphery into the nuclear interior corresponds with activation of these regions, the molecular mechanisms that mediate detachment of chromatin from the lamina, increased accessibility to these regions, and transcriptional activation are unknown. Here, we utilize a growth factor signaling model to investigate how extracellular signals are transmitted through kinase cascades to influence epigenetic changes that modulate gene expression. We provide evidence that growth factor-stimulated upregulation in the transcript levels of many responsive genes is accompanied by increases in histone phosphorylation levels, specifically at H3K9me2S10 (histone H3 Serine 10 when the adjacent Lysine 9 is dimethylated). Imaging and proteomic approaches show that Epidermal Growth Factor (EGF) stimulation results in H3K9me2S10 phosphorylation, which occurs in genomic regions enriched for regulatory enhancers of EGF-responsive genes. We also demonstrate that the EGF-induced increase in H3K9me2S10ph is dependent on the nuclear kinase MSK2, and this subset of EGF-induced genes is dependent on MSK2 for transcription. Taken together, our work indicates that growth factor-induced changes in chromatin state can mediate the activation of downstream genes and has broader implications for understanding how lineage-specific genes and regulatory elements within H3K9me2-modified chromatin may be accessed during development.