Characterizing crosstalk in epigenetic signaling to understand disease physiology

Abstract

Epigenetics, the inheritance of genomic information independent of DNA sequence, controls the interpretation of extracellular and intracellular signals in cell homeostasis, proliferation and differentiation. On the chromatin level, signal transduction leads to changes in epigenetic marks, such as histone post-translational modifications (PTMs), DNA methylation and chromatin accessibility to regulate gene expression. Crosstalk between different epigenetic mechanisms, such as that between histone PTMs and DNA methylation, leads to an intricate network of chromatin-binding proteins where pre-existing epigenetic marks promote or inhibit the writing of new marks. The recent technical advances in mass spectrometry (MS) -based proteomic methods and in genome-wide DNA sequencing approaches have broadened our understanding of epigenetic networks greatly. However, further development and wider application of these methods is vital in developing treatments for disorders and pathologies that are driven by epigenetic dysregulation.

Keywords: chromatin; epigenetics; histones; mass spectrometry; post translational modification; proteomics.

Figure 1.

Illustration summarizing the reported human, mouse, and rat histone PTMs. Modified with permission from [386]. Updated modifications are from [28,104,131,387,388].

Figure 2.

Combinatorial histone PTM patterns. In the cis-histone pattern, PTMs are found on the same histone molecule. In trans-histone (internucleosome) the PTMs occur on different nucleosomes, and in the trans-histone (intranucleosome) on the same nucleosome. Adapted from [134].

Figure 3.

Histone MS approaches based on the size of input. In bottom-up and middle-down methods, peptides are first fragmented to 5–10 aa and 20–50 aa fragments, respectively. In top-down method, intact proteins are used as input. Benefits and limitations of each method are listed.