Chromatin modification alters gene expression; therefore, scientists can add histone-modifying enzymes, histone variants, and chromatin remodeling complexes to somatic cells to aid reprogramming into pluripotent stem (iPS) cells.

Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone deacetylases or histone methyltransferases are added to increase the reprogramming efficiency. Similar to histone methylation, DNA methylation also causes chromatin compaction. Inhibitors of DNA methylases help loosen the chromatin and allow the expression of genes essential for pluripotency.

Histone variants can also be added to alter the gene expression pattern. Variants, such as H2AZ and H3.3, change gene expression because they have different amounts of DNA wound around them, allowing specific genes to be more accessible. Additionally, H2AZ often has increased acetylation, enabling more transcription factors to bind to DNA and enhancing reprogramming.