Chromatin‐modifying drugs and metabolites in cell fate control

Abstract

For multicellular organisms, it is essential to produce a variety of specialized cells to perform a dazzling panoply of functions. Chromatin plays a vital role in determining cellular identities, and it dynamically regulates gene expression in response to changing nutrient metabolism and environmental conditions. Intermediates produced by cellular metabolic pathways are used as cofactors or substrates for chromatin modification. Drug analogues of metabolites that regulate chromatin‐modifying enzyme reactions can also regulate cell fate by adjusting chromatin organization. In recent years, there have been many studies about how chromatin‐modifying drug molecules or metabolites can interact with chromatin to regulate cell fate. In this review, we systematically discuss how DNA and histone‐modifying molecules alter cell fate by regulating chromatin conformation and propose a mechanistic model that explains the process of cell fate transitions in a concise and qualitative manner.

Targeting Epigenetic Regulatory Enzymes for Cancer Therapeutics: Novel Small-Molecule Epidrug Development

“…In preclinical experiments, many small-molecule compounds have been screened as potential HATis to regulate histone acetylation and reduce tumor growth ( Table 3 ). These compounds include isothiazolone-based chemical compounds, the natural compounds garcinol and embelin ( 108 , 109 ), the pyrazolone-containing small molecule C646 ( 124 ), and the pyridoisothiazole derivatives PU139 and PU141, which block PCAF and/or p300 ( 110 ). For example, PU139 retards the growth of NB by blocking Gcn5, PCAF, CBP, and p300 ( 110 ).…”

The Metabaging Cycle

“…Inflammation will promote IR, resulting in more lipolysis and accelerated hyperlipidemia. [7][8][9] Excessive hyperlipidemia will upregulate fatty acid oxidation (FAO) in myocytes and fibro-adipogenic progenitor (FAP) cells, the intermediates and side products of which can regulate cell fate by regulating epigenetic modifications, 10,11 thus influencing them to differentiate into adipocytes or myofibroblasts, impairing muscle regeneration and aggravating muscle dysfunction. Hyperlipidemia also leads to muscle lipid infiltration, which not only results in myosteatosis in the form of intramyocellular lipid (IMCL) droplets and intermuscular adipose tissue (IMAT), but also overloads the skeletal muscle mitochondria.…”

The Potential of Induced Pluripotent Stem Cells to Treat and Model Alzheimer’s Disease

“…However, the use of earlier passages of iPSC is favored in a therapeutic application to avoid genetic and epigenetic changes that arise during the extended culturing process. A different approach would be to use a chromatin-modifying compound that enables a DNA demethylation agent, such as 5-aza-cytidine [192], to remove the methylation that is tissue specific, restoring the ability to differentiate to various tissue lineages [193]. However, this approach does not improve the pluripotency and potentially damages other regions of DNA that are susceptible to modifications.…”