Nuclear and chromatin reorganization during cell senescence and aging - a mini-review

Abstract

Genetic material in the nucleus governs mechanisms related to cell proliferation, differentiation, and function. Thus, senescence and aging are directly tied to the change of nuclear function and structure. The most important mechanisms that affect cell senescence are: (i) telomere shortening; (ii) environmental stress-mediated accumulation of DNA mutations, and (iii) the intrinsically encoded biological clock that dictates lifespan events of any particular cell type. Overall, these changes lead to modification of the expression of genes that are responsible for: (i) organization of the nuclear structure; (ii) integrity of transcriptionally inactive heterochromatin, and (iii) epigenetic modification of chromosomes due to DNA methylation and/or histone modifications. These aging-related nuclear alterations do not only affect somatic cells. More importantly, they affect stem cells, which are responsible for proper tissue rejuvenation. In this review, we focus on epigenetic changes in the chromatin structure and their impact on the biology and function of adult cells as they age. We will also address aging-related changes in a compartment of the most primitive pluripotent stem cells that were recently identified by our team and named 'very small embryonic/epiblast-like stem cells'.

Fig. 1

Aging-associated nuclear alterations as a result of intrinsic and external factors. Both intrinsic factors (e.g. telomere shortening, epigenetic modulators, and an increase in INK4a/ARF expression) as well as external factors (e.g. free radicals (ROS), ultraviolet (UV) mutagens, and some endocrine signals) lead to changes in the nuclear architecture and chromatin organization. This leads to changes in expression of aging-associated genes that impact cell function and lead to accumulation of senescent cells in various tissues.

Fig. 2

Aging affects pools of somatic and stem cells. Somatic cells undergo an agerelated process of telomere shortening and epigenetic modification of their genetic material. The stem cell compartment is affected by decreases in the number and function of pluripotent stem cell populations (e.g. VSELs) as well as by epigenetic changes in a pool of tissue-committed stem cells. Overall, the age-related nuclear alterations in the stem cell compartment are more relevant for those somatic cells that show a short half-life duration (e.g. hematopoietic cells, intestinal epithelium, and keratinocytes). However, such a nuclear alteration also affects tissues and organs that show even relatively low cell turnover (e.g. heart, brain, skeletal muscles).

Fig. 3

The unique DNA methylation pattern and expression of imprinted genes in VSELs. a Schematic diagram of paternally (Igf2-H19 and Rasgrf1, upper panel) and maternally (Igf2R and Kcnq1) methylated loci. Arrow indicates the active transcription from indicated genes. DMR = Differential methylated regions, M = maternal chromosome, P = paternal chromosome, KvDMR = DMR for Kcnq1 locus. b Bisulfite sequencing results of DNA methylation of DMR1 for Igf2-H19 locus in the indicated cells (VSELs = very small embryonic like stem cells, HSC = hematopoietic stem cells, BMMNC = bone marrow mononuclear cells). Methylated and unmethylated CpG sites are shown in filled and open circles, respectively. The numbers under the bisulfite sequencing results indicate the percentage of methylated CpG sites. c The DNA methylation level of DMRs for imprinted genes. Mean values for percentage of methylated CpG sites are shown as the mean ± SD from at least three independent experiments. ∗ p < 0.05, ∗∗ p < 0.01 compared to BMMNCs. d RQ-PCR analysis of H19, Igf2, Igf2R, and p57^KIP2 in the indicated cells. Relative quantification of the expression level of the imprinted genes was performed with the 2^−ΔΔCt method, using the mRNA level of 2-microglobulin as an endogenous control gene and that of BMMNCs as a calibrator. The relative expression level is represented as the fold difference to the value of BMMNCs and shown as the mean ± SD from at least four independent experiments on different samples of FACS sorted VSELs, HSCs, and BMMNCs. ∗ p < 0.05, ∗∗ p < 0.01 compared to BMMNCs.