Polyploidy and chromatin remodeling in hepatocytes from insulin‐dependent diabetic and normoglycemic aged mice

Abstract

Changes in polyploidization, chromatin supraorganization, and chromatin accessibility were investigated in hepatocytes collected from adult, nonobese diabetic (NOD) mice with increasing hyperglycemia and compared with adult normoglycemic controls and 56-week-old normoglycemic BALB/c mice. Our goal was to determine the changes in ploidy degrees and chromatin characteristics in mouse hepatocytes that are associated with insulin-dependent diabetes and to detect similarities in these aspects with those verified with aging, with greater accuracy than previous studies. Image analysis of Feulgen-stained nuclei revealed changes in ploidy degrees and chromatin supraorganization. Chromatin accessibility was assessed with micrococcal nuclease (MNase) digestion. Increased polyploidy was associated with increasing levels of glycemia, and this trend toward polyploidy was found even under normoglycemic conditions in NOD mice. Although high degrees of ploidy were also detected in aged BALB/c mice, the magnitude of polyploidy was not the same magnitude as that in the diabetic mice. While there was increased homogeneity of chromatin packaging with increasing polyploidy under conditions of severe hyperglycemia (and even under conditions of normoglycemia) in NOD mice, an inverse relationship was observed in aged BALB/c mice. Chromatin accessibility to MNase increased under severe hyperglycemia and advanced age, but it was much higher in the diabetic mice. In conclusion, although similarities in polyploidy were observed between the hepatocytes from increasingly hyperglycemic adult mice and those from normoglycemic aged mice, the relationship between chromatin remodeling and increases in ploidy degrees was not the same between the hepatocytes of these two groups. These findings demonstrate that strict similarities between diabetes and aging are not always true at the cellular level. This discordance is likely due to differences in the metabolic state of mouse hepatocytes during aging and diabetic conditions consequent to specificities in their gene regulatory programs. '

Feulgen-DNA content and chromatin organization in the spermathecal glands of Apis mellifera (Hymenoptera, Apoidea) queens with aging

“…A change in chromatin condensation and spatial distribution of high and medium density chromatin components has also been reported with image analysis procedures to be associated with the aging process in the housefly (Panno and Nair 1984). Considering that chromatin remodeling may reflect altered gene modulation (Dejligbjerg et al 2008;Felisbino et al 2011;Ghiraldini et al 2012Ghiraldini et al , 2014, the functional properties of the spermathecal glands of the honeybee queens would certainly be affected by aging. It could be hypothesized that by promoting a protective mechanism against increased oxidative stress in the cells, other cellular functions may be impaired by elevated polyploidization (Anatskaya and Vinogradov 2010), interfering, for instance, with the production of secretions required for the efficiency of sperm-cell preservation in the spermatheca.…”

“…In mouse liver cells, where increased polyploidization is also a well-known characteristic of aging (Gupta 2000;Anatskaya and Vinogradov 2010;Moraes et al 2007;Ghiraldini et al 2012), 122 genes are up-regulated and 77 genes are down-regulated due to aging ). Among the downregulated genes with a ≥2-fold change, several genes were found to be related to signal transduction, transcription, post-translational modifications, and inflammatory responses, and at least four genes were found to be related to chromatin structure and dynamics .…”

“…Chromatin remodeling estimated by image analysis parameters (chromatin entropy, for instance) has been described in aging mouse liver and neurons in association with changes in their gene expression (Ghiraldini et al 2012Rodrigues et al 2014). Significant changes in several chromatin image features have been determined with image analysis in neurons and Malpighian tubule cells of the aging housefly (Panno and Nair 1984).…”

Changes in Chromatin Structure along Aging

“…It means that neurons from different regions of brain can have their own genetic programs according to their specific functions or localization, and therefore, could age differently from the others, showing diverse age-associated chromatin configurations. Other studies have found no age-related change in chromatin organization for whole brain, liver, kidney or heart tissue [42,43], or chromatin unpackaging for mouse hepatocytes with aging [44], when subjected to nuclease digestion. It was argued that the non-dividing nature of these cells could be an explanation, since when aged skin fibroblasts were analyzed under the same approach, changes in chromatin organization were found (i.e.…”

Genomic profiling of type-1 adult diabetic and aged normoglycemic mouse liver

“…Hyperglycemia promotes chromatin remodeling and increased polyploidy levels in hepatocytes from non-obese diabetic (NOD) mice; these alterations are similar, but not identical, to the changes observed in hepatocytes from old mice [5]. Recently, it has been observed that the alterations in chromatin organization that occur in hepatocytes from hyperglycemic NOD mice might be orchestrated by the NAD + -dependent histone deacetylases Sirt1 and Sirt6 [6].…”