Translational research : the journal of laboratory and clinical medicine
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The developmental regulation of globin gene expression has served as an important model for understanding higher eukaryotic transcriptional control mechanisms. During human erythroid development, there is a sequential switch from expression of the embryonic ε-globin gene to the fetal ɣ-globin gene in utero, and postpartum the ɣ-globin gene is silenced, as the β-globin gene becomes the predominantly expressed locus. Because the expression of normally silenced fetal ɣ-type globin genes and resultant production of fetal hemoglobin (HbF) in adult erythroid cells can ameliorate the pathophysiological consequences of both abnormal β-globin chains in sickle cell anemia and deficient β-globin chain production in β-thalassemia, understanding the complex mechanisms of this developmental switch has direct translational clinical relevance. ⋯ Much of the information about epigenetic silencing stems from studies of globin gene regulation. As discussed here, the term epigenetics refers to postsynthetic modifications of DNA and chromosomal histone proteins that affect gene expression and can be inherited through somatic cell replication. A full understanding of the molecular mechanisms of epigenetic silencing of HbF expression should facilitate the development of more effective treatment of β-globin chain hemoglobinopathies.
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Mammalian messenger RNA (mRNA) and long noncoding RNA (lncRNA) contain tens of thousands of posttranscriptional chemical modifications. Among these, the N(6)-methyl-adenosine (m(6)A) modification is the most abundant and can be removed by specific mammalian enzymes. m(6)A modification is recognized by families of RNA binding proteins that affect many aspects of mRNA function. mRNA/lncRNA modification represents another layer of epigenetic regulation of gene expression, analogous to DNA methylation and histone modification.
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The study of epigenetics is intimately linked and inseparable from developmental biology. Many of the genes that imprint epigenetic information on chromatin function during the specification of cell lineages in the developing embryo. These include the histone methyltransferases and their cofactors of the Polycomb and Trithorax gene families. ⋯ In adult tissues, histone methylation marks must be maintained for normal gene expression patterns. In chronic and acute renal disease, epigenetic marks are being characterized and correlated with the establishment of metabolic memory, in part to explain the persistence of pathologies even when optimal treatment modalities are used. Thus, the state of the epigenome in adult cells must be considered when attempting to alleviate or alter gene expression patterns in disease.
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Idiopathic pulmonary fibrosis (IPF) is a complex lung disease of unknown etiology. Development of IPF is influenced by both genetic and environmental factors. Recent work by our and other groups has identified strong genetic predisposition factors for the development of pulmonary fibrosis, and cigarette smoke remains the most strongly associated environmental exposure risk factor. ⋯ Moreover, epigenetic marks represent a promising therapeutic target for IPF. In this review, the disease is introduced, genetic and gene expression studies in IPF are summarized, exposures relevant to IPF and known epigenetic changes associated with cigarette smoke exposure are discussed, and epigenetic studies conducted so far in IPF are summarized. Limitations, challenges, and future opportunities in this field are also discussed.
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Persistent or chronic pain is tightly associated with various environmental changes and linked to abnormal gene expression within cells processing nociceptive signaling. Epigenetic regulation governs gene expression in response to environmental cues. Recent animal model and clinical studies indicate that epigenetic regulation plays an important role in the development or maintenance of persistent pain and possibly the transition of acute pain to chronic pain, thus shedding light in a direction for development of new therapeutics for persistent pain.