43.5:
Chromatin Modification in iPS Cells
Scientists experimentally induce chromatin remodeling to enhance the conversion of cells into pluripotent stem cells. Chromatin is composed of nucleosomes—structures consisting of DNA wound around histone proteins.
Remodeling transforms the condensed chromatin to a relaxed form, inducing the gene expression necessary for pluripotency.
During remodeling, the histones are modified by specific enzymes, and entire nucleosomes relocate, altering gene expression.
Methylation strengthens the interaction between histones and DNA, suppressing transcription of genes involved in differentiation. In contrast, histone demethylases remove methyl groups to activate genes involved in pluripotency.
Unlike methylation, acetylation weakens histones’ interaction with DNA and loosens the chromatin to make it accessible to transcription factors. Histone acetyltransferases and deacetylases catalyze acetylation and deacetylation.
Histone variants can replace the major histone proteins, leading to chromatin remodeling. For example, when the variant H2AZ is incorporated into the nucleosome it increases the accessibility of DNA to specific transcription factors and promotes the conversion of somatic cells to iPS cells.
43.5:
Chromatin Modification in iPS Cells
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.
Suggested Reading
- Dong, F., Song, Z., Yu, J., Zhang, B., Jiang, B., Shen, Y., Lu, Y., Song, C., Cong, P., & Liu, H. (2016). Dynamic Changes in Occupancy of Histone Variant H2A.Z during Induced Somatic Cell Reprogramming. Stem cells international, 2016, 3162363.
- Sha K, Boyer LA. The chromatin signature of pluripotent cells. 2009 May 31. In: StemBook [Internet]. Cambridge (MA): Harvard Stem Cell Institute; 2008