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PubMed2025

Immune dysfunction in Alzheimer disease.

Emerging evidence highlights the crucial role of peripheral immune cells in maintaining brain homeostasis and their influence on the pathology of Alzheimer disease (AD). Genome-wide association studies have identified numerous AD risk variants in genes expressed by immune cells, implicating innate and adaptive immune pathways in disease progression. Advances in neuroimmunology have revealed that immune cell crosstalk involving T cells, B cells, monocytes and/or macrophages and neutrophils can modulate the hallmark features of AD, including amyloid plaque accumulation, tau pathology and chronic neuroinflammation. Mechanistic insights suggest that chronic peripheral inflammation, immune exhaustion, metabolic dysfunction and epigenetic reprogramming exacerbate neurodegeneration in AD by promoting toxic inflammation and impairing protein clearance in the brain. These findings may catalyse the development of novel immunomodulatory strategies, such as immune checkpoint inhibition and cytokine targeting, among others, for AD. This Review examines peripheral immune alterations in AD, evaluates related therapeutic opportunities and highlights key knowledge gaps, particularly the need for human-derived data to advance translational progress. Future research should prioritize personalized approaches that integrate genetic risk, immune profiling and ageing to inform next-generation therapies for AD.

Humans↗
PubMed2005

Poly(ADP-ribose): a co-regulator of DNA methylation?

The formation of multiprotein complexes is l'ordre du jour in regulatory pathways. In this issue of Oncogene, Reale et al. report the formation of a particularly sophisticated complex of two important regulatory enzymes, DNMT1 (DNA methyltransferase-1) and PARP-1 (poly(ADP-ribose)polymerase-1). The former evolved with a specific sequence motif binding the enzymatic product of the latter. The product, poly(ADP-ribose), bonds the two partners into a heterodimeric complex and, as a consequence, the catalytic function of DNMT1 is silenced. Thus, PARP-1 becomes a conditional negative regulator of DNMT1. In a larger perspective, Reale et al. highlight the potential role of PARP-1 as a co-regulator of DNA methylation leading to epigenetic reprogramming of cancer cells.

Animals↗
PubMed2005

Messenger RNA expression patterns in bovine embryos derived from in vitro procedures and their implications for development.

The preimplantation bovine embryo is initially under the control of maternal genomic information that is accumulated during oogenesis. The genetic programme of development soon becomes dependent on new transcripts derived from activation of the embryonic genome. The early steps in development, including the timing of the first cleavage, activation of the embryonic genome, compaction and blastocyst formation, can be affected by the culture media and conditions, as well as the production procedure itself. These perturbations can possibly result in a marked decrease in the quality of the resulting blastocysts and may even affect the viability of offspring born after transfer. In vitro procedures such as in vitro production and somatic nuclear transfer of bovine embryos have been shown to be correlated with significant up- or downregulation, de novo induction or silencing of genes critical for undisturbed fetal and neonatal development. These alterations are likely to be caused by epigenetic modifications, such as DNA methylation and histone modifications. Analysis of perturbed epigenetic reprogramming and of the related phenomena, such as genomic imprinting and X-chromosome inactivation, in bovine embryos is promising for understanding the underlying mechanisms of developmental abnormalities, such as large offspring syndrome.

Animals↗
PubMed2000

Spatial separation of parental genomes in preimplantation mouse embryos.

We have used two different experimental approaches to demonstrate topological separation of parental genomes in preimplantation mouse embryos: mouse eggs fertilized with 5-bromodeoxyuridine (BrdU)-labeled sperm followed by detection of BrdU in early diploid embryos, and differential heterochromatin staining in mouse interspecific hybrid embryos. Separation of chromatin according to parental origin was preserved up to the four-cell embryo stage and then gradually disappeared. In F1 hybrid animals, genome separation was also observed in a proportion of somatic cells. Separate nuclear compartments during preimplantation development, when extreme chromatin remodelling occurs, and possibly in some differentiated cell types, may be associated with epigenetic reprogramming.

Animals↗
PubMed2002

Intracytoplasmic sperm injection may increase the risk of imprinting defects.

In germ cells and the early embryo, the mammalian genome undergoes widespread epigenetic reprogramming. Animal studies suggest that this process is vulnerable to external factors. We report two children who were conceived by intracytoplasmic sperm injection (ICSI) and who developed Angelman syndrome. Molecular studies, including DNA methylation and microsatellite and quantitative Southern blot analysis, revealed a sporadic imprinting defect in both patients. We discuss the possibility that ICSI may interfere with the establishment of the maternal imprint in the oocyte or pre-embryo.

Adult↗
PubMed2026

Molecular Regulation of Primordial Germ Cell Specification and Implications for In Vitro Gametogenesis.

Primordial germ cells (PGCs) are the embryonic precursors of gametes, essential for transmitting genetic and epigenetic information across generations. However, PGC specification occurs within a narrow developmental window and involves only a small number of cells, making it difficult to study in vivo. In vitro models using pluripotent stem cells have enabled the generation of primordial germ cell-like cells, but these systems often rely on exogenous signaling and exhibit variability in efficiency and epigenetic fidelity. In this review, we synthesize current understanding of PGC specification in mouse and human systems, emphasizing the integration of signaling pathways, transcriptional networks, epigenetic reprogramming, and metabolic regulation. Canonical regulators, including PRDM1, PRDM14, TFAP2C, and SOX17, function within a broader, interconnected network that establishes for PGC competence. Understanding these interactions will be crucial for advancing in vitro gametogenesis and improving mammalian reproduction.

mammalian reproduction↗
PubMed2004

Genome-wide demethylation destabilizes CTG.CAG trinucleotide repeats in mammalian cells.

Many neurological diseases, including myotonic dystrophy, Huntington's disease and several spinocerebellar ataxias, result from intergenerational increases in the length of a CTG.CAG repeat tract. Although the basis for intergenerational repeat expansion is unclear, repeat tracts are especially unstable during germline development and production of gametes. Mammalian development is characterized by waves of genome-wide demethylation and remethylation. To test whether changes in methylation status might contribute to trinucleotide repeat instability, we examined the effects of DNA methyltransferase inhibitors on trinucleotide repeat stability in mammalian cells. Using a selectable genetic system for detection of repeat contractions in CHO cells, we showed that the rate of contractions increased >1000-fold upon treatment with the DNA methyltransferase inhibitor 5-aza-deoxycytidine (5-aza-CdR). The link between DNA demethylation and repeat instability was strengthened by similar results obtained with hydralazine treatment, which inhibits expression of DNA methyltransferase. In human cells from myotonic dystrophy patients, treatment with 5-aza-CdR strongly destabilized repeat tracts in the DMPK gene, with a clear bias toward expansion. The bias toward expansion events and changes in repeat length that occur in jumps, rather than by accumulation of small changes, are reminiscent of the intergenerational repeat instability observed in human patients. The dramatic destabilizing effect of DNA methyltransferase inhibitors supports the hypothesis that changes in methylation patterns during epigenetic reprogramming may trigger the intergenerational repeat expansions that lead to disease.

Animals↗
PubMed2005

Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer.

Hsp90 is a chaperone for over 100 'client proteins' in the cell, most of which are involved in signaling pathways. For example, Hsp90 maintains several nuclear hormone receptors, such as the estrogen receptor (ER), as agonist-receptive monomers in the cytoplasm. In the presence of agonist, Hsp90 dissociates and the receptors dimerize, enter the nucleus and ultimately activate transcription of the target genes. Increasing evidence suggests that Hsp90 also has a role in modifying the chromatin conformation of many genes. For example, Hsp90 has recently been shown to increase the activity of the histone H3 lysine-4 methyltransferase SMYD3, which activates the chromatin of target genes. Further evidence for chromatin-remodeling functions is that Hsp90 acts as a capacitor for morphological evolution by masking epigenetic variation. Release of the capacitor function of Hsp90, such as by environmental stress or by drugs that inhibit the ATP-binding activity of Hsp90, exposes previously hidden morphological phenotypes in the next generation and for several generations thereafter. The chromatin-modifying phenotypes of Hsp90 have striking similarities to the trans-generational effects of the ER agonist diethylstilbesterol (DES). Prenatal and perinatal exposure to DES increases the predisposition to uterine developmental abnormalities and cancer in the daughters and granddaughters of exposed pregnant mice. In this review, we propose that trans-generational epigenetic phenomena involving Hsp90 and DES are related and that chromatin-mediated WNT signaling modifications are required. This model suggests that inhibitors of Hsp90, WNT signaling and chromatin-remodeling enzymes might function as anticancer agents by interfering with epigenetic reprogramming and canalization in cancer stem cells.

Animals↗
PubMed2005

Comparative birth weights of singletons born after assisted reproduction and natural conception in previously infertile women.

BACKGROUND: The possible interference of assisted reproduction techniques (ART) with epigenetic reprogramming during early embryo development has recently sparked renewed interest about the reported lower birth weight among infants born as a consequence of infertility treatments. However, the latter finding so far has relied on the comparison of the birth weight of infants conceived with ART to general population data. A more appropriate comparison group should involve pregnancies in infertile women after natural conception. Therefore, we compared neonatal birth weight data of infants born after various ART treatments, including intrauterine insemination (IUI), with those of previously infertile women achieving pregnancy after sexual intercourse. METHODS: Between August 1996 and March 2004 the data of all infertile women presenting in the infertility unit of the University Women's Hospital of Basel, Switzerland, were collected prospectively, adding up to 995 intact pregnancies and deliveries. The birth weight of all infants resulting from 741 singleton pregnancies were analysed with regard to the patients' characteristics, the occurrence of complications during pregnancy and the type of infertility treatment with which the pregnancies were achieved. RESULTS: Comparison of duration of pregnancy and birth weight of infants born after infertility treatment confirms a shorter pregnancy span and a lower mean birth weight in infants born after IVF and ICSI. If women with pregnancies after ART deliver before term, neonatal birth weight is significantly lower. CONCLUSIONS: There is a specific effect of ART, mainly IVF and ICSI, on both shortening the duration of pregnancy and lowering neonatal birth weight. Both these parameters seem to be interrelated consequences of some modification in the gestational process induced by the infertility treatment. Freezing and thawing of oocytes in the pronucleate stage had a lesser impact on pregnancy span and on neonatal birth weight.

Adult↗
PubMed2002

Epigenetic marks at BRCA1 and p53 coding sequences in early human embryogenesis.

In the vertebrate genome, methylation of deoxycytosine residues of CpGs dinucleotide has been associated with transcriptional silencing of genes, parental imprinting, X-inactivation and chromatin remodelling. In human somatic tissues, the 5' end of the BRCA1 CpG island is methylated, whereas this region is unmethylated in mature germ cells and early embryos. In gametes, as in somatic tissues, the CpG sites in the coding region are methylated. We took advantage of this bimodal distribution as a model to analyse the epigenetic reprogramming of coding regions during early human embryogenesis using the bisulphite-based genomic sequencing method. During preimplantation divisions, exon 11 of BRCA1 was slowly demethylated and retained approximately 30% of its methylated residues at the blastocyst stage. Moreover, the change in the distribution of methylated residues was not restricted to the BRCA1 gene, since for another gene, p53, a relatively high level of methylation (50%) of exon 4 was observed in blastocysts. Taken together, these data suggest that a significant part of the methylated residues of coding sequences might be conserved during preimplantation development.

Animals↗
PubMed2026

Navigating the base excision repair pathway in chromatin-focus on oxidative DNA damage.

Chromatin environment influences all nuclear processes, including DNA repair. Conversely, DNA damage itself triggers chromatin modifications and remodeling, which are essential for efficient DNA repair and its coordination with transcription, replication, and epigenetic regulation to preserve genome function. While chromatin dynamics associated with double-strand break repair and nucleotide excision repair are well understood, those accompanying base excision repair (BER) remain comparatively poorly characterized. Yet, BER is responsible for eliminating a wide spectrum of chemically diverse and non-helix-distorting base modifications, arising from both endogenous and exogenous sources, and is implicated in numerous pathologies. This review examines how BER operates in the context of chromatin, with a focus on its interplay with other repair factors, chromatin modifications, and remodeling. It also explores the diversity of BER substrates, the blurred distinction between base lesions and programmed modifications, and the intricate link between BER, transcriptional regulation, and epigenetic reprogramming. Together, these insights highlight BER's pivotal role in maintaining genome stability, shaping transcriptional programs, and preventing disease.

Excision Repair↗
PubMed1994

Advances and controversies in the study of programmed cell death/apoptosis in the development of and therapy for cancer.

Whether normal or malignant, cells possess within their repertoire of epigenetic programs the ability to undergo a process of cellular suicide, termed programmed cell death. This programmed cell death process involves an epigenetic reprogramming of the cell that results in an energy-dependent cascade of biochemical and morphologic changes within the cell (also termed apoptosis), resulting in its death and elimination. Activation of programmed cell death is controlled by a series of endogenous cell-type-specific signals. In addition, various exogenous cell-damaging treatments (eg, radiation, chemicals, and viruses) can activate this pathway if sufficient injury to the cell occurs.

Apoptosis↗
PubMed2003

The basis of natural and artificial postzygotic hybridization barriers in Arabidopsis species.

The success or failure of interspecific crosses is vital to evolution and to agriculture, but much remains to be learned about the nature of hybridization barriers. Several mechanisms have been proposed to explain postzygotic barriers, including negative interactions between diverged sequences, global genome rearrangements, and widespread epigenetic reprogramming. Another explanation is imbalance of paternally and maternally imprinted genes in the endosperm. Interspecific crosses between diploid Arabidopsis thaliana as the seed parent and tetraploid Arabidopsis arenosa as the pollen parent produced seeds that aborted with the same paternal excess endosperm phenotype seen in crosses between diploid and hexaploid A. thaliana. Doubling maternal ploidy restored seed viability and normal endosperm morphology. However, substituting a hypomethylated tetraploid A. thaliana seed parent reestablished the hybridization barrier by causing seed abortion and a lethal paternal excess phenotype. We conclude from these findings that the dominant cause of seed abortion in the diploid A. thaliana x tetraploid A. arenosa cross is parental genomic imbalance. Our results also demonstrate that manipulation of DNA methylation can be sufficient to erect hybridization barriers, offering a potential mechanism for speciation and a means of controlling gene flow between species.

Arabidopsis↗
PubMed2004

Extensive maternal DNA hypomethylation in the endosperm of Zea mays.

A PCR-based genomic scan has been undertaken to estimate the extent and ratio of maternally versus paternally methylated DNA regions in endosperm, embryo, and leaf of Zea mays (maize). Analysis of several inbred lines and their reciprocal crosses identified a large number of conserved, differentially methylated DNA regions (DMRs) that were specific to the endosperm. DMRs were hypomethylated at specific methylation-sensitive restriction sites upon maternal transmission, whereas upon paternal transmission, the methylation levels were similar to those observed in embryo and leaf. Maternal hypomethylation was extensive and offers a likely explanation for the 13% reduction in methyl-cytosine content of the endosperm compared with leaf tissue. DMRs showed identity to expressed genic regions, were observed early after fertilization, and maintained at a later stage of endosperm development. The implications of extensive maternal hypomethylation with respect to endosperm development and epigenetic reprogramming will be discussed.

Binding Sites↗
PubMed2005

DNA methyltransferase 3b regulates nerve growth factor-induced differentiation of PC12 cells by recruiting histone deacetylase 2.

To elucidate the role of epigenetic reprogramming in cell- or tissue-specific differentiation, we explored the role of DNA methyltransferases (Dnmts) in the nerve growth factor (NGF)-induced differentiation of PC12 (pheochromocytoma) cells into neuronal cells. The mRNA and protein levels of de novo methyltransferase Dnmt3b increased, whereas those of Dnmt3a and Dnmt1 decreased, during NGF-induced neurite outgrowth. Dnmt3b localized in the nucleus, as well as in the growing neurites. When the expression of Dnmt3b was inhibited by antisense or small interfering RNA, PC12 cells continued to proliferate and failed to generate neurites. Cells depleted of Dnmt3b were unable to exit the cell cycle even after 6 days of NGF treatment. Furthermore, this failure in differentiation correlated with significant attenuation in tyrosine phosphorylation of TrkA (a marker for NGF-induced differentiation) and reduced the expression of neuronal markers, Hu antigen, and MAP2. The methyl-CpG content of the PC12 genome or the methylation status of repetitive elements was not significantly altered after differentiation and was not affected by Dnmt3b depletion. This was consistent with the ability of the catalytic-site mutant of Dnmt3b to induce differentiation in Dnmt3b-depleted cells after NGF treatment. The Dnmt3b-mediated differentiation was attributed to its N-terminal domain, which recruits histone deacetylase 2 (Hdac2), as demonstrated by (i) impeding of differentiation by the Hdac inhibitors, (ii) facilitation of the differentiation process by overexpression of the N-terminal domain of Dnmt3b, (iii) higher Hdac activity associated with Dnmt3b after NGF treatment, and (iv) coimmunoprecipitation and cosedimentation of Dnmt3b specifically with Hdac2 in a glycerol density gradient. These data indicate a novel role of Dnmt3b in neuronal differentiation.

Animals↗
PubMed2006

Epigenetic tête-à-tête: the bilateral relationship between chromatin modifications and DNA methylation.

The epigenome, which comprises chromatin, associated proteins, and the pattern of covalent modification of DNA by methylation, sets up and maintains gene expression programs. It was originally believed that DNA methylation was the dominant reaction in determining the chromatin structure. However, emerging data suggest that chromatin can affect DNA methylation in both directions, triggering either de novo DNA methylation or demethylation. These events are particularly important for the understanding of cellular transformation, which requires a coordinated change in gene expression profiles. While genetic alterations can explain some of the changes, the important role of epigenetic reprogramming is becoming more and more evident. Cancer cells exhibit a paradoxical coexistence of global loss of DNA methylation with regional hypermethylation.

Acetylation↗
PubMed2000

Experimental condensation inhibition in constitutive and facultative heterochromatin of mammalian chromosomes.

What drives the dramatic changes in chromosome structure during the cell cycle is one of the oldest questions in genetics. During mitosis, all chromosomes become highly condensed and, as the cell completes mitosis, most of the chromatin decondenses again. Only chromosome regions containing constitutive or facultative heterochromatin remain in a more condensed state throughout interphase. One approach to understanding chromosome condensation is to experimentally induce condensation defects. 5-Azacytidine (5-aza-C) and 5-azadeoxycytidine (5-aza-dC) drastically inhibit condensation in mammalian constitutive heterochromatin, in particular in human chromosomes 1, 9, 15, 16, and Y, as well as in facultative heterochromatin (inactive X chromosome), when incorporated into late-replicating DNA during the last hours of cell culture. The decondensing effects of 5-aza-C analogs, which do not interfere with normal base pairing in substituted duplex DNA, have been correlated with global DNA hypomethylation. In contrast, decondensation of constitutive heterochromatin by incorporation of 5-iododeoxyuridine (IdU) or other non-demethylating base analogs, or binding of AT-specific DNA ligands, such as berenil and Hoechst 33258, may reflect an altered steric configuration of substituted or minor-groove-bound duplex DNA. Consequently, these compounds exert relatively specific effects on certain subsets of AT-rich constitutive heterochromatin, i.e. IdU on human chromosome 9, berenil on human Y, and Hoechst 33258 on mouse chromosomes, which provide high local concentrations of IdU incorporation sites or DNA-ligand-binding sites. None of these non-demethylating compounds affect the inactive X chromosome condensation. Structural features of chromosomes are largely determined by chromosome-associated proteins. In this light, we propose that both DNA hypomethylation and steric alterations in chromosomal DNA may interfere with the binding of specific proteins or multi-protein complexes that are required for chromosome condensation. The association between chromosome condensation defects, genomic instability, and epigenetic reprogramming is discussed. Chromosome condensation may represent a key ancestral mechanism for modulating chromatin structure that has since been realloted to other nuclear processes.

Animals↗
PubMed2006

Global DNA hypermethylation-associated cancer chemotherapy resistance and its reversion with the demethylating agent hydralazine.

BACKGROUND: The development of resistance to cytotoxic chemotherapy continues to be a major obstacle for successful anticancer therapy. It has been shown that cells exposed to toxic concentrations of commonly used cancer chemotherapy agents develop DNA hypermethylation. Hence, demethylating agents could play a role in overcoming drug resistance. METHODS: MCF-7 cells were rendered adriamycin-resistant by weekly treatment with adriamycin. Wild-type and the resulting MCF-7/Adr cells were analyzed for global DNA methylation. DNA methyltransferase activity and DNA methyltransferase (dnmt) gene expression were also determined. MCF-7/Adr cells were then subjected to antisense targeting of dnmt1, -3a, and -b genes and to treatment with the DNA methylation inhibitor hydralazine to investigate whether DNA demethylation restores sensitivity to adriamycin. RESULTS: MCF-7/Adr cells exhibited the multi-drug resistant phenotype as demonstrated by adriamycin resistance, mdr1 gene over-expression, decreased intracellular accumulation of adriamycin, and cross-resistance to paclitaxel. The mdr phenotype was accompanied by global DNA hypermethylation, over-expression of dnmt genes, and increased DNA methyltransferase activity as compared with wild-type MCF-7 cells. DNA demethylation through antisense targeting of dnmts or hydralazine restored adriamycin sensitivity of MCF-7/Adr cells to a greater extent than verapamil, a known inhibitor of mdr protein, suggesting that DNA demethylation interferes with the epigenetic reprogramming that participates in the drug-resistant phenotype. CONCLUSION: We provide evidence that DNA hypermethylation is at least partly responsible for development of the multidrug-resistant phenotype in the MCF-7/Adr model and that hydralazine, a known DNA demethylating agent, can revert the resistant phenotype.

Journal Article↗