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At least 217 records · Page 12Linked to original sources
PubMed2004

DNA methylation as a therapeutic target in hematologic disorders: recent results in older patients with myelodysplasia and acute myeloid leukemia.

DNA methylation provides a major epigenetic code (besides histone modification) of the lineage- and development-specific genes (such as regulators of differentiation in the hematopoietic lineages) that control expression of normal cells. However, DNA methylation is also involved in malignancies because aberrant methylating gene activity occurs during leukemic transformation. Thus, genes such as tumor suppressor genes, growth-regulatory genes, and adhesion molecules are often silenced in various hematopoietic malignancies by epigenetic inactivation via DNA hypermethylation. This inactivation is frequently seen not only in transformed cell lines but also in primary leukemia cells. Because this defect is amenable to reversion by pharmacologic means, agents that inhibit DNA methylation have been developed to specifically target this hypermethylation defect in leukemia and preleukemia cases. The most clinically advanced agents, the azanucleosides 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine), were discovered more than 25 years ago, when their methylation-inhibitory activities, even at low concentrations, became apparent. Although both of these agents, like cytarabine, had been clinically used until then at high doses, the redevelopment of these agents for low-dose schedules has revealed very interesting clinical activities for treating myelodysplasia (MDS) and acute myeloid leukemia (AML). Because these diseases occur mostly in patients over 60 years of age, low-dose schedules with these compounds provide a very promising approach in such patient groups by virtue of their low nonhematologic toxicity profiles. In the present review, we describe the development of treatments that target DNA hypermethylation in MDS and AML, and clinical results are presented. In addition, pharmacologic DNA demethylation may be viewed as a platform for biological modification of malignant cells to become sensitized (or resensitized) to secondary signals, such as differentiating signals (retinoids, vitamin D3) and hormonal signals (eg, estrogen receptor in breast cancer cells, androgen receptor in prostate cancer cells). Finally, an in vitro synergism between the reactivating potency of demethylating agents and inhibitors of histone deacetylation has been tested in several pilot studies of AML and MDS treatment. Finally, gene reactivation by either group of compounds results in therapeutically meaningful reactivation of fetal hemoglobin in patients with severe hemoglobinopathies, extending the therapeutic range of derepressive epigenetic agents to nonmalignant hematopoietic disorders.

Antineoplastic Agents↗
PubMed2003

Cancer and epigenesis: a developmental perspective.

Traditionally, molecular geneticists have studied the genome, that is, DNA. This has included its sequencing, with identification of promoters, enhancers, introns, exons, and mutations. During the last 10 to 15 years, it has become clear that this study of "naked" DNA imposed major limitations on our understanding of gene regulation, and that DNA must be studied in conjunction with its protein backbone (chromatin). This new vision has shown that chromatin is a very dynamic molecule, and that changes in DNA methylation, in histones leg, their localization, density, and whether they are acetylated, methylated, phosphorylated and/or ubiquitinated), and in the Polycomb-Trithorax equilibrium are all crucial for the control of gene expression. Furthermore, it was found that like DNA, chromatin-related proteins and DNA methylation are generally passed on unchanged from one cell to its daughters. Thus, gene expression is partly controlled through chromatin modifications that are transmitted from one cell to all its descendants. Such a control is referred to as "epigenetic," as the DNA sequence is not altered. Hence, these epigenetic "marks" can be erased in the early embryo, rendering these cells totipotent. This chapter presents a basic overview of epigenesis in the control of normal embryonal cell differentiation, including imprinting. Similarities between embryonal and cancer cells are highlighted, and the potential impact of chemotherapy aimed at epigenetic mechanisms is reviewed.

Alleles↗
PubMed2000

Core histones of the amitochondriate protist, Giardia lamblia.

Genes coding for the core histones H2a, H2b, H3, and H4 of Giardia lamblia were sequenced. A conserved organism- and gene-specific element, GRGCGCAGATTTVGG, was found upstream of the coding region in all core histone genes. The derived amino acid sequences of all four histones were similar to their homologs in other eukaryotes, although they were among the most divergent members of this protein family. Comparative protein structure modeling combined with energy evaluation of the resulting models indicated that the G. lamblia core histones individually and together can assume the same three-dimensional structures that were established by X-ray crystallography for Xenopus laevis histones and the nucleosome core particle. Since G. lamblia represents one of the earliest-diverging eukaryotes in many different molecular trees, the structure of its histones is potentially of relevance to understanding histone evolution. The G. lamblia proteins do not represent an intermediate stage between archaeal and eukaryotic histones.

Amino Acid Motifs↗
PubMed2003

Genetic control of developmental changes induced by disruption of Arabidopsis histone deacetylase 1 (AtHD1) expression.

Little is known about the role of genetic and epigenetic control in the spatial and temporal regulation of plant development. Overexpressing antisense Arabidopsis thaliana HD1 (AtHD1) encoding a putative major histone deacetylase induces pleiotropic effects on plant growth and development. It is unclear whether the developmental abnormalities are caused by a defective AtHD1 or related homologs and are heritable in selfing progeny. We isolated a stable antisense AtHD1 (CASH) transgenic line and a T-DNA insertion line in exon 2 of AtHD1, resulting in a null allele (athd1-t1). Both athd1-t1 and CASH lines display increased levels of histone acetylation and similar developmental abnormalities, which are heritable in the presence of antisense AtHD1 or in the progeny of homozygous (athd1-t1/athd1-t1) plants. Furthermore, when the athd1-t1/athd1-t1 plants are crossed to wild-type plants, the pleiotropic developmental abnormalities are immediately restored in the F(1) hybrids, which correlates with AtHD1 expression and reduction of histone H4 Lys12 acetylation. Unlike the situation with the stable code of DNA and histone methylation, developmental changes induced by histone deacetylase defects are immediately reversible, probably through the restoration of a reversible histone acetylation code needed for the normal control of gene regulation and development.

Arabidopsis↗
PubMed2025

Post-translational modifications of the nucleoid protein H-NS: sites, mechanisms, and regulatory cues.

Histone-like nucleoid structuring protein H-NS plays a pivotal role in orchestrating bacterial chromatin and regulating horizontal gene transfer (HGT) elements. In response to environmental signals, H-NS undergoes dynamic post-translational modifications (PTMs) that resemble the epigenetic codes of eukaryotic histones. This review explores how environmental cues regulate PTMs at specific sites within distinct domains of H-NS, thereby modulating its oligomerization and DNA-binding capabilities to reprogram bacterial responses. Notably, HGT elements commonly encode counter-silencing factors, including PTM-modifying enzymes, that counteract H-NS repression. We propose that combinatorial PTM patterns on H-NS form the bacterial histone-like epigenetic code, regulating the expression of HGT elements. Collectively, these interactions establish a sophisticated network of silencing and counter-silencing mechanisms that drive bacterial genome evolution.

Protein Processing, Post-Translational↗