Cytosine modifications in myeloid malignancies.

Aberrant DNA methylation is a hallmark of many cancers, including the myeloid malignancies acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The discovery of TET-mediated demethylation of 5-methylcytosine (5mC) and technological advancements in next-generation sequencing have permitted the examination of other cytosine modifications, namely 5-hydroxymethylcytosine (5hmC), in these myeloid malignancies on a genome-wide scale. Due to the prominence of mutations in epigenetic modifiers that can influence cytosine modifications in these disorders, including IDH1/2, TET2, and DNMT3A, many recent studies have evaluated the relative levels, distribution, and functional consequences of cytosine modifications in leukemic cells. Furthermore, several therapies are being used to treat AML and MDS that target various proteins within the cytosine modification pathway in an effort to revert the abnormal epigenetic patterns that contribute to the diseases. In this review, we provide an overview of cytosine modifications and selected technologies currently used to distinguish and analyze these epigenetic marks in the genome. Then, we discuss the role of mutant enzymes, including DNMT3A, TET2, IDH1/2, and the transcription factor, WT1, in disrupting normal patterns of 5mC and 5hmC in AML and MDS. Finally, we describe several therapies, both standard, front-line treatments and new drugs in clinical trials, aimed at inhibiting the proteins that ultimately lead to aberrant cytosine modifications in these diseases.

Epigenetic deregulation in myeloid malignancies.

Abnormal epigenetic patterning commonly is observed in cancer, including the myeloid malignancies acute myeloid leukemia and myelodysplastic syndromes. However, despite the universal nature of epigenetic deregulation, specific subtypes of myeloid disorders are associated with distinct epigenetic profiles, which accurately reflect the biologic heterogeneity of these disorders. In addition, mutations and genetic alterations of epigenetic-modifying enzymes frequently have been reported in these myeloid malignancies, emphasizing the importance of epigenetic deregulation in the initiation, progression, and outcome of these disorders. These aberrant epigenetic modifiers have become new targets for drug design, because their inhibition can potentially reverse the altered epigenetic landscapes that contribute to the development of the leukemia. In this review, we provide an overview of the role of epigenetic deregulation in leukemic transformation and their potential for therapeutic targeting.

DNA methylation and histone modifications are associated with repression of the inhibin α promoter in the rat corpus luteum.

The transition from follicle to corpus luteum after ovulation is associated with profound morphological and functional changes and is accompanied by corresponding changes in gene expression. The gene encoding the α subunit of the dimeric reproductive hormone inhibin is maximally expressed in the granulosa cells of the preovulatory follicle, is rapidly repressed by the ovulatory LH surge, and is expressed at only very low levels in the corpus luteum. Although previous studies have identified transient repressors of inhibin α gene transcription, little is known about how this repression is maintained in the corpus luteum. This study examines the role of epigenetic changes, including DNA methylation and histone modification, in silencing of inhibin α gene expression. Bisulfite sequencing reveals that methylation of the inhibin α proximal promoter is low in preovulatory and ovulatory follicles but is elevated in the corpus luteum. Increased methylation during luteinization is observed within the cAMP response element in the promoter, and EMSA demonstrate that methylation of this site inhibits cAMP response element binding protein binding in vitro. Chromatin immunoprecipitation reveals that repressive histone marks H3K9 and H3K27 trimethylation are increased on the inhibin α promoter in primary luteal cells, whereas the activation mark H3K4 trimethylation is decreased. The changes in histone modification precede the alterations in DNA methylation, suggesting that they facilitate the recruitment of DNA methyltransferases. We show that the DNA methyltransferase DNMT3a is present in the ovary and in luteal cells when the inhibin α promoter becomes methylated and observe recruitment of DNMT3a to the inhibin promoter during luteinization.