Post-translational modifications (PTMs) to histone proteins constitute a major type of epigenetic mechanism that regulates chromatin structure and gene expression patterns in eukaryotes. In addition to their important roles in standard physiology, disruptions in histone PTM signaling patterns have been suggested to be significant, potentially causative factors in various human diseases such as cancer. As most histone PTM work in the chromatin biology field is accomplished using site-specific antibodies, the quantitative measurement of combinational histone PTMs co-occurring on the same molecule has been unmet. Our objectives include the continued development of mass spectrometry-based proteomics and bioinformatic methods for quantitatively interrogating combinatorial histone PTM patterns, and applying these approaches to investigate histone mediated epigenetics mechanisms behind key areas of health related biological research. Here we will specifically apply our approaches to investigate epigenetic histone PTM signaling during human embryonic stem cell differentiation.
Our specific aims are three in number and include identifying changing histone PTMs during stem cell differentiation, characterizing combinatorial histone PTM binding protein complexes that translate these PTM patterns, and determining the role of these combinatorial PTMs in maintaining the pluripotent state or facilitating to a specific lineage We expect that these comprehensive proteomic strategies will continue to generate new tools to study epigenetic histone PTMs and generate novel insights into the mechanism of combinatorial histone PTMs in gene regulation during diverse biological events such as cellular differentiation.
Histone post-translational modifications (PTMs) are an intensely investigated research field and alterations in these PTM patterns have been suggested to play roles in the pathology of some diseases, or in developmental biology. This research will help establish the role of these PTMs in human biology, and will impact areas such as regenerative medicine and cancer biology, thus laying down the foundation for potential development of epigenetic therapy.
|Sidoli, Simone; Garcia, Benjamin A (2017) Middle-down proteomics: a still unexploited resource for chromatin biology. Expert Rev Proteomics 14:617-626|
|Kori, Yekaterina; Sidoli, Simone; Yuan, Zuo-Fei et al. (2017) Proteome-wide acetylation dynamics in human cells. Sci Rep 7:10296|
|Sidoli, Simone; Kulej, Katarzyna; Garcia, Benjamin A (2017) Why proteomics is not the new genomics and the future of mass spectrometry in cell biology. J Cell Biol 216:21-24|
|Fiziev, Petko; Akdemir, Kadir C; Miller, John P et al. (2017) Systematic Epigenomic Analysis Reveals Chromatin States Associated with Melanoma Progression. Cell Rep 19:875-889|
|Kim, Joseph J; Bennett, Neal K; Devita, Mitchel S et al. (2017) Optical High Content Nanoscopy of Epigenetic Marks Decodes Phenotypic Divergence in Stem Cells. Sci Rep 7:39406|
|Karch, Kelly R; Langelier, Marie-France; Pascal, John M et al. (2017) The nucleosomal surface is the main target of histone ADP-ribosylation in response to DNA damage. Mol Biosyst 13:2660-2671|
|Liu, Monica Yun; Torabifard, Hedieh; Crawford, Daniel J et al. (2017) Mutations along a TET2 active site scaffold stall oxidation at 5-hydroxymethylcytosine. Nat Chem Biol 13:181-187|
|Klein, Brianna J; Simithy, Johayra; Wang, Xiaolu et al. (2017) Recognition of Histone H3K14 Acylation by MORF. Structure 25:650-654.e2|
|Coradin, Mariel; Karch, Kelly R; Garcia, Benjamin A (2017) Monitoring proteolytic processing events by quantitative mass spectrometry. Expert Rev Proteomics 14:409-418|
|Dorighi, Kristel M; Swigut, Tomek; Henriques, Telmo et al. (2017) Mll3 and Mll4 Facilitate Enhancer RNA Synthesis and Transcription from Promoters Independently of H3K4 Monomethylation. Mol Cell 66:568-576.e4|
Showing the most recent 10 out of 79 publications