Changes In Histone Methylation Patterns Research Articles

Histone 3 Trimethylation Patterns are Associated with Resilience or Stress Susceptibility in a Rat Model of Major Depression Disorder.

Major Depressive Disorder (MDD) is a severe and multifactorial psychiatric condition. Evidence has shown that environmental factors, such as stress, significantly explain MDD pathophysiology. Studies have hypothesized that changes in histone methylation patterns are involved in impaired glutamatergic signaling. Based on this scenario, this study aims to investigate histone 3 involvement in depression susceptibility or resilience in MDD pathophysiology by investigating cellular and molecular parameters related to i) glutamatergic neurotransmission, ii) astrocytic functioning, and iii) neurogenesis. For this, we subjected male Wistar rats to the Chronic Unpredictable Mild Stress (CUMS) model of depression. We propose that by evaluating the sucrose consumption, open field, and object recognition test performance from animals submitted to CUMS, it is possible to predict with high specificity rats with susceptibility to depressive-like phenotype and resilient to the depressive-like phenotype. We also demonstrated, for the first time, that patterns of H3K4me3, H3K9me3, H3K27me3, and H3K36me3 trimethylation are strictly associated with the resilient or susceptible to depressive-like phenotype in a brain-region-specific manner. Additionally, susceptible animals have reduced DCx and GFAP and resilient animals present increase of AQP-4 immunoreactivity. Together, these results provide evidence that H3 trimethylations are related to the development of the resilient or susceptible to depressive-like phenotype, contributing to further advances in the pathophysiology of MDD and the discovery of mechanisms behind resilience.

Myeloid Leukemogenesis Driven by Aberrant CDX2 Expression Involves Transcriptional Repression of KLF4 and Deregulated PPARγ Signaling

Abstract 1355 Background:Aberrant expression of the developmental regulatory gene CDX2 in the adult hematopoietic compartment occurs in 90% of acute myeloid leukemia (AML) cases and promotes leukemogenesis. In contrast, CDX2 acts as a tumor suppressor in the colon and rectum. The effectors that mediate the leukemogenic activity of CDX2, as well as the mechanistic basis for the disparate functions of CDX2 in AML and colorectal cancer, remain largely unknown. Methods: DNA microarrays were used to characterize a gene signature that was activated in mouse hematopoetic stem and progenitor cells in response to enforced Cdx2 expression, in a murine model of Cdx2-induced leukemia, and in human AML associated with aberrant CDX2 expression. The functional role of candidate CDX2 effectors was evaluated by lentiviral gene knockdown and overexpression in myeloid leukemia and colon cancer cell lines. The interaction of CDX2 with putative target genes was examined by chromatin immunoprecipitation. A chemical-genomic analysis based on the Connectivity Map was used to identify drugs that may reverse CDX2-induced transcriptional changes. Results: A cross-species analysis of murine and human transcriptome data identified repression of the zinc-finger transcription factor KLF4 as an essential component of the CDX2 signature. KLF4 was silenced by CDX2, and restoration of KLF4 expression induced cell cycle arrest and apoptosis selectively in myeloid leukemia cells expressing CDX2. In contrast to AML, KLF4 is positively regulated by CDX2 in colonic epithelial cells, and consistent with its tissue-specific properties, CDX2 was found to bind to distinct sites in the KLF4 upstream regulatory region in AML versus colon cancer cells, which induced antagonistic changes in histone methylation patterns at the KLF4 promoter. A Connectivity Map analysis revealed that the transcriptional changes induced by CDX2 in hematopoietic cells are counteracted by drugs that stimulate the nuclear receptor PPARγ. Of potential therapeutic value, PPARγ agonists upregulate KLF4 expression and are preferentially toxic to CDX2-expressing myeloid leukemia cells, which were found to display altered PPARγ signaling both in vitro and in vivo. Conclusions: These data delineate the transcriptional program associated with CDX2 expression in hematopoietic cells, identify KLF4 as a reciprocally controlled AML suppressor gene, and uncover reactivation of KLF4 expression, through modulation of PPARγ signaling, as a novel therapeutic modality in CDX2-driven AML. Furthermore, these observations indicate that transcriptional regulators like CDX2 may have opposing effects on carcinogenesis in different tissues due to differential regulation of their downstream targets. Disclosures:No relevant conflicts of interest to declare.

Epigenetics: deciphering its role in diabetes and its chronic complications.

1. Increasing evidence suggests that epigenetic factors might regulate the complex interplay between genes and the environment, and affect human diseases, such as diabetes and its complications. 2. Clinical trials have underscored the long lasting beneficial effects of strict glycaemic control for reducing the progression of diabetic complications. They have also shown that diabetic complications, such as diabetic nephropathy, a chronic kidney disorder, can continue even after blood glucose normalization, suggesting a metabolic memory of the prior glycaemic state. 3. Dysregulation of epigenetic post-transcriptional modifications of histones in chromatin, including histone lysine methylation, has been implicated in aberrant gene regulation associated with the pathology of diabetes and its complications. Genome-wide studies have shown cell-type specific changes in histone methylation patterns under diabetic conditions. In addition, studies in vascular cells have shown long lasting changes in epigenetic modifications at key inflammatory gene promoters after prior exposure to diabetic conditions, suggesting a possible mechanism for metabolic memory. 4. Recent studies have shown roles for histone methylation, DNA methylation, as well as microRNA in diabetic nephropathy. Whether these epigenetic factors play a role in metabolic memory of diabetic kidney disease is less well understood. 5. The incidence of diabetes is growing rapidly, as also the cost of treating the resulting complications. A better understanding of metabolic memory and the potential involvement of epigenetic mechanisms in this phenomenon could enable the development of new therapeutic targets for the treatment and/or prevention of sustained diabetic complications.

Epigenetic control of plant development by Polycomb-group proteins

Recent genetic studies indicate that the plant Polycomb-group genes play much broader roles in development than was initially apparent from their single mutant phenotypes. At the mechanistic level, evidence is accumulating that their protein products act together in complexes that direct changes in histone methylation patterns. We discuss recent studies that give clues as to how these epigenetic changes are propagated through mitosis, how they are interpreted, and how they might be reset.

Transcriptional inhibitors affecting topoisomerase II induce changes in histone methylation patterns similar to those induced by heat shock

The relationship between gene expression and the patterns of histone methylation in Drosophila cells has been investigated using inhibitors of transcription acting at various levels. Inhibition of ribosomal RNA synthesis and processing by 5-fluorouridine or of general RNA synthesis by camptothecin, an inhibitor of topoisomerase I, does not affect the methylation pattern of core histones. This suggests that the arrest of transcription per se is not involved in the changes in histone methylation such as those encountered in heat-shocked cells. However, ethidium bromide and novobiocin, which are known to disrupt nucleosome structure, and VM-26 (teniposide), a specific inhibitor of topoisomerase II, induce changes in histone methylation patterns which, though less severe, are similar to those observed under cellular stress. These results suggest that chromatin conformation is probably an important factor in the accessibility of histones to methyltransferases.