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Results for “Epigenetic memory”

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PubMed1986

Strong effects of 5-azacytidine on the in vitro lifespan of human diploid fibroblasts.

Azacytidine (5-aza-CR) and azadeoxycytidine (5-aza-CdR) are known to inhibit the methylation of cytosine (5-mC) in DNA, and their effects on the long-term growth of human fibroblasts, strain MRC-5, have been examined. A single treatment with either analogue initially inhibits growth, but the cells recover to normal morphology, growth rate and cell density at confluence. However, a memory of the treatment is retained, since the cells' subsequent lifespan is considerably reduced in comparison with controls, and the terminal stages of growth are indistinguishable from senescent cultures of untreated cells. The effect of 5-aza-CR or 5-aza-CdR does not appear to be closely related to the concentration used, or to the length of treatment up to about half-way through the total lifespan. Sequential doses have cumulative effects on longevity. There is evidence that the pattern of 5-mC in mammalian DNA is inherited via cell division; therefore, a reduction in 5-mC induced by a pulse treatment of 5-aza-CR or 5-aza-CdR will be transmitted to all descendants. The results are consistent with independent observations that the level of 5-mC declines continually during the serial subculture of human diploid cells. The analogues would be expected to precipitate this decline and thereby advance the physiological age of the culture. The results provide support for the view that the random loss of methyl groups in DNA may eventually have deleterious consequences, such as aberrant epigenetic changes in gene expression.

5-Methylcytosine↗

PubMed2001

Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization.

Mental function has as its cerebral basis a specific dynamic structure. In particular, cortical and limbic areas involved in "higher brain functions" such as learning, memory, perception, self-awareness and consciousness continuously need to be self-adjusted even after development is completed. By this lifelong self-optimization process, the cognitive, behavioural and emotional reactivity of an individual is stepwise remodelled to meet the environmental demands. While the presence of rigid synaptic connections ensures the stability of the principal characteristics of function, the variable configuration of the flexible synaptic connections determines the unique, non-repeatable character of an experienced mental act. With the increasing need during evolution to organize brain structures of increasing complexity, this process of selective dynamic stabilization and destabilization of synaptic connections becomes more and more important. These mechanisms of structural stabilization and labilization underlying a lifelong synaptic remodelling according to experience, are accompanied, however, by increasing inherent possibilities of failure and may, thus, not only allow for the evolutionary acquisition of "higher brain function" but at the same time provide the basis for a variety of neuropsychiatric disorders. It is the objective of the present paper to outline the hypothesis that it might be the disturbance of structural brain self-organization which, based on both genetic and epigenetic information, constantly "creates" and "re-creates" the brain throughout life, that is the defect that underlies Alzheimer's disease (AD). This hypothesis is, in particular, based on the following lines of evidence. (1) AD is a synaptic disorder. (2) AD is associated with aberrant sprouting at both the presynaptic (axonal) and postsynaptic (dendritic) site. (3) The spatial and temporal distribution of AD pathology follows the pattern of structural neuroplasticity in adulthood, which is a developmental pattern. (4) AD pathology preferentially involves molecules critical for the regulation of modifications of synaptic connections, i.e. "morphoregulatory" molecules that are developmentally controlled, such as growth-inducing and growth-associated molecules, synaptic molecules, adhesion molecules, molecules involved in membrane turnover, cytoskeletal proteins, etc. (5) Life events that place an additional burden on the plastic capacity of the brain or that require a particularly high plastic capacity of the brain might trigger the onset of the disease or might stimulate a more rapid progression of the disease. In other words, they might increase the risk for AD in the sense that they determine when, not whether, one gets AD. (6) AD is associated with a reactivation of developmental programmes that are incompatible with a differentiated cellular background and, therefore, lead to neuronal death. From this hypothesis, it can be predicted that a therapeutic intervention into these pathogenetic mechanisms is a particular challenge as it potentially interferes with those mechanisms that at the same time provide the basis for "higher brain function".

Alzheimer Disease↗

PubMed2002

Chromatin reprogramming of male somatic cell-derived XIST and TSIX in ES hybrid cells.

In mammalian somatic cells, the X chromosome is active in XY males, whereas one X chromosome is inactivated in XX females. On the active male X chromosome, the XIST and TSIX genes are transcribed in undifferentiated cells of pre-implantation embryos (undifferentiated state) and then down-regulated upon cell differentiation (differentiated state). To explore the epigenetic mechanism involved in the on-off switching of XIST and TSIX transcription in the active X chromosome, male somatic cells were hybridized with male embryonic stem (ES) cells. Fluorescence in situ hybridization analysis revealed that the XIST gene derived from somatic cells was derepressed, as shown by the advent of two pinpoint signals. This was confirmed by strand-specific RT-PCR of XIST and TSIX genes. To analyze changes in chromatin structure in the promoter regions of XIST and TSIX derived from somatic cells, histone tail modifications were studied by chromatin immunoprecipitation analysis. Histones H3 and H4, which were hypoacetylated in the somatic cells, were hyperacetylated in the hybrid cells, and histone H3 lysine 4, which was hypomethylated in the somatic cells, was hypermethylated in the hybrid cells, indicating that the reactivation of XIST and TSIX was linked with chromatin modifications. In the telomeric region of DXPAS34, acetylation of histones H3 and H4 was dependent on reactivation of XIST and TSIX, whereas histone H3 lysine 4 was constitutively methylated independent of the transcriptional activity of those genes. We propose that the chromatin reprogramming is linked with the resetting of the memory found in the process of choosing an active X chromosome.

Animals↗

PubMed2006

Methylation of the IL-12Rbeta2 gene as novel tumor escape mechanism for pediatric B-acute lymphoblastic leukemia cells.

Previous studies have shown that the interleukin-12 receptor beta2 (IL-12Rbeta2) gene is expressed in normal naive, germinal center and memory B cells but not in their malignant counterparts. The aim of this study was to investigate (i) whether the IL-12Rbeta2 gene is silenced in B-cell acute lymphoblastic leukemia (B-ALL) cells, and (ii) what the functional implications of such silencing for tumor growth are. Here, we show that although mature B cells expressed both chains of the IL-12R, normal pro-B and pre-B cells failed to express the IL-12Rbeta2 chain. Similarly, primary tumor cells from pediatric pro-B, early pre-B, and pre-B ALL (30 cases) did not express the IL-12Rbeta2 chain. IL-12Rbeta2 gene silencing in B-ALL was found to depend on methylation of a CpG island in exon 1. Such methylation was not detected in normal early B cells that when differentiated into mature B cells expressed the IL-12Rbeta2 gene. Detection of IL-12Rbeta2 mRNA and protein in the tumorigenic 697 pre-B-ALL cell line allowed to perform functional experiments in severe combined immunodeficient/nonobese diabetic mice receiving 697 cells with or without human recombinant IL-12 (hrIL-12). hrIL-12 administration reduced tumor growth and metastasis through antiproliferative and proapoptotic rather than antiangiogenic, activities. In conclusion, epigenetic silencing of the IL-12Rbeta2 gene represents a novel mechanism of tumor escape for B-ALL cells.

Animals↗

PubMed2026

Respiratory viral infections prime accelerated lung cancer growth.

The COVID-19 pandemic has highlighted the long-term consequences of viral pneumonia, yet its impact on cancer development remains unclear. Here, we show that patients previously hospitalized with severe COVID-19 have an increased risk of subsequent lung cancer. Across multiple murine models, severe respiratory viral infections accelerated lung cancer growth, whereas vaccination mitigated infection-enhanced tumor progression. Mechanistically, prior viral pneumonia reprogrammed the lung into a pro-tumor microenvironment marked by the sustained accumulation of tumor-associated neutrophils and heightened immunosuppression. We observed persistent chromatin remodeling at key cytokine loci in immune and structural cells, linking inflammatory memory to tumor-promoting signals. Therapeutically, combined blockade of neutrophil recruitment and programmed death-ligand 1 (PD-L1) restored CD8+ T cell function and suppressed tumor growth. Together, these findings establish a causal link between prior viral pneumonia and lung tumorigenesis, underscoring the need for enhanced surveillance and targeted interventions to reduce post-COVID cancer risk.

Animals↗

PubMed2000

The older patient in psychoanalysis.

The demographic shift toward extended longevity has led to a commensurate increase in the length of the working and productive years, and with it an increase in the number of so-called "older" patients who come into psychoanalysis or psychoanalytic psychotherapy. This led the Psychoanalytic Research and Development Fund to support a four-year study by a small group of experienced psychoanalysts of "the older patient in psychoanalysis." Aging and old age are considered to be the final developmental crisis of the successive epigenetic phases of the life cycle. Eleven case presentations and various briefer clinical vignettes informed us that older and even old individuals, who seek treatment themselves or who are appropriately referred, respond in a positive and effective fashion to psychoanalysis and psychoanalytic psychotherapy. As do younger patients in analysis, such older people, motivated by the wish to make the most of what time is left, become interested in understanding their pasts with respect to the present and the future. The life stories of two older men who undertook analysis, and the courses and outcomes of their analyses, illustrate our findings and impressions. In both cases conflicts and difficulties from earlier developmental phases, extending back even as far as the oedipal and preoedipal years, were revived during their older years. And although these conflicts might have been beyond definitive resolution, what is salient is the extent to which they were ameliorated: sufficiently that they did not impede a satisfactory adaptive solution of the final crisis of the normative sequences of the life cycle.

Aged↗

PubMed2005

Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report.

DNA methylation changes could provide a mechanism for DNA plasticity and dynamism for short-term adaptation, enabling a type of cell memory to register cellular history under different environmental conditions. Some environmental insults may also result in pathological methylation with corresponding alteration of gene expression patterns. Evidence from several studies has suggested that in schizophrenia and bipolar disorder, mRNA of the reelin gene (RELN), which encodes a protein necessary for neuronal migration, axonal branching, synaptogenesis, and cell signaling, is severely reduced in post-mortem brains. Therefore, we investigated the methylation status of the RELN promoter region in schizophrenic patients and normal controls as a potential mechanism for down regulation of its expression. Ten post-mortem frontal lobe brain samples from male schizophrenic patients and normal controls were obtained from the Harvard Brain Tissue Resources Center. DNA was extracted using a standard phenol-chloroform DNA extraction protocol. To evaluate differences between patients and controls, we applied methylation specific PCR (MSP) using primers localized to CpG islands flanking a potential cyclic AMP response element (CRE) and a stimulating protein-1 (SP1) binding site located in the promoter region. For each sample, DNA extraction, bisulfite treatment, and MSP were independently repeated at least four times to accurately determine the methylation status of the target region. Forty-three PCR trials were performed on the test and control samples. MSP analysis of the RELN promoter revealed an unmethylated signal in all reactions (43 of 43) using DNA from the frontal brain tissue, derived from either the schizophrenic patients or normal controls indicating that this region of the RELN promoter is predominantly unmethylated. However, we observed a distinct methylated signal in 73% of the trials (16 of 22) in schizophrenic patients compared with 24% (5 of 21) of controls. Thus, the hypermethylation of the CpG islands flanking a CRE and SP1 binding site observed at a significantly higher level (t = -5.07, P = 0.001) may provide a mechanism for the decreased RELN expression, frequently observed in post-mortem brains of schizophrenic patients. We also found an inverse relationship between the level of DNA methylation using MSP analysis and the expression of the RELN gene using semi-quantitative RT-PCR. Despite the small sample size, these studies indicate that promoter hypermethylation of the RELN gene could be a significant contributor in effecting epigenetic alterations and provides a molecular basis for the RELN gene hypoactivity in schizophrenia. Further studies with a larger sample set would be required to validate these preliminary observations.

Adult↗