SUMO and Chromatin Remodeling.

Many of the known SUMO substrates are nuclear proteins, which regulate gene expression and chromatin dynamics. Sumoylation, in general, appears to correlate with decreased transcriptional activity, and in many cases modulation of the chromatin template is implicated. Sumoylation of the core histones is associated with transcriptional silencing, and transcription factor sumoylation can decrease gene expression by promoting recruitment of chromatin modifying enzymes. Additionally, sumoylation of transcriptional corepressors and chromatin remodeling enzymes can influence interactions with other transcriptional regulators, and alter their enzymatic activity. In some cases, proteins that are components of transcriptional corepressor complexes have been shown to be SUMO E3 ligases, further emphasizing the integration of sumoylation with the regulation of chromatin remodeling. Despite the evidence suggesting that sumoylation is primarily repressive for access to chromatin, recent analyses suggest that protein sumoylation on the chromatin template may play important roles at highly expressed genes. Elucidating the dynamic interplay of sumoylation with other post-translational modifications of histones and chromatin associated proteins will be key to fully understanding the regulation of access to the chromatin template.

Restoring SIRT6 Expression in Hutchinson-Gilford Progeria Syndrome Cells Impedes Premature Senescence and Formation of Dysmorphic Nuclei.

OBJECTIVES: Mice overexpressing SIRT6 live longer than wild-type mice while SIRT6 knockout mice exhibit similar degenerative phenotypes as individuals with Hutchinson-Gilford progeria syndrome (HGPS). Thus, we sought to test whether levels of SIRT6 are reduced in cells from individuals with HGPS and whether restored SIRT6 expression may impede premature aging phenotypes. METHODS: Levels of endogenous SIRT6 and progerin in HGPS and normal fibroblasts were assessed by Western blotting and immunofluorescence. A tetracycline-inducible system was utilized to test whether progerin causes a rapid reduction in SIRT6 protein. SIRT6 was overexpressed in HGPS cells via lentiviral infection with biological endpoints including senescence-associated ß-galactosidase (SA-ß-gal) positivity, frequency of nuclear atypia, the number of 53BP1-positive DNA damage foci and growth rates. RESULTS: Typical HGPS fibroblasts express lower levels of SIRT6 than fibroblasts from normal and atypical HGPS donors. Experimental induction of progerin did not cause a detectable reduction of SIRT6 protein. However, overexpression of SIRT6 in HGPS cells was associated with a reduced frequency of SA-ß-gal positivity, fewer misshapen nuclei, fewer DNA damage foci, and increased growth rates. CONCLUSIONS: Typical HGPS fibroblasts exhibit reduced levels of SIRT6 protein via a mechanism that remains to be elucidated. Our findings suggest that restoring SIRT6 expression in HGPS cells may partially impede senescence and the formation of dysmorphic nuclei. © 2015 S. Karger AG, Basel.

Potential epigenetic mechanism(s) associated with the persistence of psychoneurological symptoms in women receiving chemotherapy for breast cancer: a hypothesis.

Due to recent treatment advances, there have been improvements in the proportion of women surviving a diagnosis of breast cancer (BC). However, many of these survivors report persistent adverse side effects following treatment, such as cognitive dysfunction, depressive symptoms, anxiety, fatigue, sleep disturbances, and pain. Investigators have examined circulating levels of inflammatory markers, particularly serum cytokines, for a potential causal relationship to the development/persistence of these psychoneurological symptoms (PNS). While inflammatory activation, resulting from perceived stress or other factors, may directly contribute to the development of PNS, we offer an alternative hypothesis, suggesting that these symptoms are an early step in a cascade of biological changes leading to epigenetic alterations at the level of deoxyribonucleic acid (DNA) methylation, histone modifications, and/or chromatin structure/chromosomal instability. Given that epigenetic patterns have plasticity, if this conjectured relationship between epigenomic/acquired genomic alterations and the development/persistence of PNS is confirmed, it could provide foundational knowledge for future research leading to the recognition of predictive markers and/or treatments to alleviate PNS in women with BC. In this article, we discuss an evolving theory of the biological basis of PNS, integrating knowledge related to inflammation and DNA repair in the context of genetic and epigenetic science to expand the paradigm for understanding symptom acquisition/persistence following chemotherapy.