In this review, we would like to present the overall concepts of “-omes−epi-omes” interactions, i.e., the interactions among the four most noticeable “-omes” (genome, transcriptome, proteome, and metabolome) to the four “epi-omes” (epigenome, epitranscriptome, epiproteome, and epimetabolome) as well as discussing the recently identified epimodifications in humans.With the advancement of mass spectrometry and sequencing technologies, novel epimodifications/epi-marks are gradually revealed in recent years. Nowadays, it is becoming clear that all the constituents of the genome, transcriptome, proteome, and even the metabolome can further be modified/decorated with various epi-marks. Given the fact that a variety of modifications can occur in DNA/RNA, proteins, and metabolites, it is possible that an unknown number of epimodifications/epi-marks might exist and are yet to be discovered.The ability to decipher and manipulate the epi-omes might present new avenues in drug design for procuring better treatment of various human diseases.

Zinc ion (Zn2+) is essential for life; its deficiency in the human body could cause stunted growth, anemia and susceptibility to infection. The Zn transporter ZIP8 (also known as SLC39A8) is an important Zn2+ importer; aberrant Zn2+ influx mediated by ZIP8 can lead to the pathogenesis of osteoarthritis and inflammatory diseases. ZIP8 also mediates the cellular uptake of divalent metal ions including iron, manganese, and the toxic heavy metal cadmium. Individuals with SLC39A8 mutations and transgenic mouse models are starting to reveal the critical role that this gene plays in embryonic development and the metabolism of essential metal ions. Here we summarize our current understanding of ZIP8's function and regulation, at both the molecular and biological levels. We also review the association of ZIP8 with various diseases and its linkage with complex disorders like obesity, hypertension, and schizophrenia as revealed by several large genome-wide association studies.

Human exposures to cadmium (Cd) compounds are common in the living environment. Cd is toxic, yet, little is known about its effect at the lung cell proteome level. Here, we provide a proteomic analysis of lung epithelial cells (LECs) treated with CdCl2, with the aim of identifying protein response to Cd toxicity. Comparative proteome analysis was conducted to identify global changes in the protein expression profiles of sham-exposed and Cd-treated cells. Proteins were separated by two-dimensional electrophoresis and visualized by silver staining. We reported that while a low level (2 μM) of Cd treatment elicited negligible cytotoxicity and produced no significant proteome changes between the treated group and the control, however, a high level (20 μM) of Cd treatment induced obvious proteome changes and cell death in LECs. Differentially-expressed proteins were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and database searching. The proteins that were significantly up-regulated included heat-shock proteins (HSPs) and antioxidative stress proteins. Pretreatment with the thiol antioxidant glutathione before Cd treatment effectively abrogated the induction of these proteins and prevented cell death. Our results demonstrate that Cd causes oxidative stress-induced cell death, and these differentially-expressed proteins are defense proteins important for fighting against the Cd toxicity, while a low level of Cd may exert a more noticeable effect after long-term exposure, but not after transient exposure.

Heat shock factors (HSFs) are vital for modulating stress and heat shock-related gene expression in cells. The activity of HSFs is controlled largely by post-translational modifications (PTMs). For example, basal phosphorylation of HSF1 on three serine sites suppresses the heat shock response, and hyperphosphorylation of HSF1 on several other serine and threonine sites by stress-activated kinases results in its activation, while acetylation on K80 inhibits its DNA-binding ability. Sumoylation of HSF2 on K82 regulates its DNA-binding ability, whereas sumoylation of HSF4B on K293 represses its transcriptional activity. With the advancement of proteomic technology, novel PTM sites on various HSFs have been identified with the use of tandem mass spectrometry (MS/MS), but the functions of many of these PTMs are still unclear. Yet, it should be noted that the discovery of these novel PTM sites provided the necessary evidence for the existence of these PTM marks in vivo. Followed by subsequent functional analysis, this would ultimately lead to a better understanding of these PTM marks. MS/MS-based proteomic approach is becoming a gold standard in PTM validation in the field of life science. Here, the recent literature of all known PTMs reported on human HSFs and the resulting functions will be discussed.