DNA can also itself be chemically modified to amplify or sup press transcription. CpG sites within gene promoter regions can be chemically modified by methylation enzymes called DNA methyl transferases (DNMTs), which decrease DNA binding of RNA polymerase and associated transcription factors. Hypermethylation has been observed in bone marrow cells of patients with myelodysplastic syndromes (MDSs), and the degree of DNA hypermethylation correlates with disease stage. In MDSs, the promoters of genes that are important for myeloid differentiation are hypermethylated, repressing their transcription and inhibiting proper maturation of the myeloid lineages. Hypomethylating agents such as azacitidine and decitabine can induce remission and may prolong survival in some MDS patients.

The regulation of gene expression by modification of chroma tin conformation or DNA itself is termed epigenetic because it tunes cell function without altering the nucleotide sequence of the DNA. Regulation and function of the epigenome and their role in hematopoiesis and diseases thereof are described in Chapter 3 and reviewed in Cullen et al.[1] Examples of hematologic malignancies driven by disordered epigenetic regulation include MDSs and acute myeloid leukemia (AML), with mutations in the DNMT3A gene observed in approximately 5% of MDSs and approximately 20% of AML cases. DNMT3A mutations confer a worse prognosis in AML. The ten eleven-translocation methylcytosine dioxygenase member, TET2, catalyzes hydroxymethylation of cytosines in DNA and results in demethylation of DNA; TET2 is mutated in AML, MDSs, chronic myelomonocytic leukemia (CMML), and other myeloproliferative neoplasms (MPNs), and all mutations represent loss-of-function mutations. Both DNTM3A and TET2 mutations, together with mutations in other chromatin modifiers such as ASXL1, can widely regulate gene expression and are often present in clonal hematopoiesis, preceding onset of frank malignancy.

References
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[1] Cullen SM, Mayle A, Rossi L, Goodell MA. Hematopoietic stem cell development: an epigenetic journey. Curr Top Dev Biol. 2014;107:39–75.

مواضيع ذات صلة

RNA Proofreading

Electrostatic Forces that Determine Protein Structure

A peptide bond

ادوات قطع ولحم الـ DNA

مصير الـ DNA الغريب في النظام البكتيري

A Common Mechanism for Splicing Reactions

آليات واهمية النقل transduction mechanisms

النقل transduction

Regulation of Transcription by Chromatin

RNA Polymerase Binding and Regulation by Transcription Factors

The Discovery of Self-Splicing RNAs

Splicing Reactions and Complexes