Long-Term Effects of Chromatin Remodeling and DNA Damage in Stem Cells Induced by Environmental and Dietary Agents

Abstract

The presence of histones acts as a barrier to protein access; thus chromatin remodeling must occur for essential processes such as transcription and replication. In conjunction with histone modifications, DNA methylation plays critical roles in gene silencing through chromatin remodeling. Chromatin remodeling is also interconnected with the DNA damage response, maintenance of stem cell properties, and cell differentiation programs. Chromatin modifications have increasingly been shown to produce long-lasting alterations in chromatin structure and transcription. Recent studies have shown environmental exposures in utero have the potential to alter normal developmental signaling networks, physiologic responses, and disease susceptibility later in life during a process known as developmental reprogramming. In this review we discuss the long-term impact of exposure to environmental compounds, the chromatin modifications that they induce, and the differentiation and developmental programs of multiple stem and progenitor cell types altered by exposure. The main focus is to highlight agents present in the human lifestyle that have the potential to promote epigenetic changes that impact developmental programs of specific cell types, may promote tumorigenesis through altering epigenetic marks, and may be transgenerational, for example, those able to be transmitted through multiple cell divisions.

Bioflavonoids promote stable translocations between MLL‐AF9 breakpoint cluster regions independent of normal chromosomal context: Model system to screen environmental risks

“…MLL breakpoint sequences associated with infant acute leukemia are similar to those in t-AML following etoposidecontaining regimens (Super et al, 1993;Broeker et al, 1996). Thus, it has been hypothesized that exposure to biochemically similar compounds including bioflavonoids may contribute to infant leukemia from in utero exposure from maternal diet (Ross, 2000;Vanhees et al, 2011;Bariar et al, 2013).…”

“…Due to their antioxidant capacity, bioflavonoids are used for their presumed health benefits, such as protection against cardiovascular diseases, cancer, and inflammation. However, they have pleiotropic effects on cells, and their direct role in any single pathway has been less clear (Bariar et al, ). Further, clear quantitation of the relative potency of compounds or their additive, synergistic, or even quenching effects on the potential to promote translocations remains unclear.…”

DNA Damage and Repair Mechanisms Triggered by Exposure to Bioflavonoids and Natural Compounds

“…The majority of studies generate targeted DSBs by endonucleases or lasers, and introduce artificial repair substrates into the system [15]. However, exposure to natural compounds can lead to multiple DSBs in a variety of chromatin regions and contexts [16][17][18][19][20]. Understanding how cells respond to these compounds and repair damage caused by them has important implications for genome stability.…”

“…Bioflavonoids are also in pesticides and flame retardants [25][26][27]. Bioflavonoids inhibit the enzyme topoisomerase II (Top2) to promote DSBs, and recent studies have elucidated the cellular mechanisms used to repair the DSBs induced by bioflavonoids [16,28,29]. This chapter will discuss cell type differences in expression and activity of proteins in major DNA repair pathways, summarize findings of cellular response to bioflavonoids and Top2 inhibition, discuss how these compounds trigger alternative end-joining, and conclude with implications for genome instability and human disease.…”

Single Low Dose Bisphosphonate Treatment Enhances Osteogenesis in hMSCs By Exerting Epigenetic Changes

“…4 This effect may bring alterations in some of the epigenetic markers, that may afterwards promote tumorigenesis and be transmitted through the cell division cycle. 5,6 Bisphosphonates (BPs) are a class of drugs that are used to treat resorptive bone diseases like osteoporosis. 7 They mainly inhibit osteoclast action by different ways.…”