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Description:
This session will highlight recent remarkable insights about ‘quieter’ more subtle regulators of globin gene expression, which are essential to a fuller understanding of human red blood cell biology and disease. Knowledge gained about the molecular regulation of erythropoiesis will continue to transform therapy in globin gene disorders, such as Sickle Cell Disease and β-Thalassemia.
Dr. Mitchell Weiss will discuss how hypoxia inducible factor 1 (HIF1) regulates red blood cell fetal hemoglobin (HbF, a2g2) expression by binding to cognate DNA elements in the BGLT3 long noncoding RNA gene located 2.7 kb downstream of the g-globin genes (HBG1 and HBG2). These findings link globin gene regulation with canonical hypoxia adaptation, provide a mechanism for HbF induction during increased erythropoietic demand (“stress erythropoiesis”), and suggest a new therapeutic approach for Sickle Cell Disease and β-Thalassemia.
Dr. Ann Dean will discuss the role of long non-coding RNAs (lncRNAs) in erythroid differentiation. LncRNAs are defined as RNA transcripts of longer than 200 nucleotides, without potential to code for a polypeptide. Nuclear lncRNAs have been found to regulate gene expression in almost all aspects, from transcription to translation, by diverse mechanisms. Dr. Dean will describe an antisense lncRNA transcribed opposite to the GATA2 gene that regulates numerous erythroid genes by interacting with erythroid transcription factors. She will also document a lncRNA transcribed from one of the enhancers of the Myb gene, an enhancer RNA or eRNA, that interacts with the co-regulator complex MLL1 to regulated Myb transcription. Loss of either of these lncRNAs results in elevated HBG1/HBG2 transcription, highlighting the potential of lncRNA manipulation as a therapeutic approach to Sickle Cell Disease and β-Thalassemia.
Dr. Gerd Blobel will summarize recent work that made use of advanced CRISPR screening tools to gain new insights into mechanisms that impinge on the switch from fetal to adult hemoglobin production in human erythroid cells. This includes new regulatory factors that act directly on the globin gene cluster as well as those that function via intermediates. Dr. Blobel will discuss the broader ramifications of this work with respect to fundamental mechanisms of developmental gene expression control and highlight the implications for new therapeutic approaches for the treatment of hemoglobinopathies.
Dr. Mitchell Weiss will discuss how hypoxia inducible factor 1 (HIF1) regulates red blood cell fetal hemoglobin (HbF, a2g2) expression by binding to cognate DNA elements in the BGLT3 long noncoding RNA gene located 2.7 kb downstream of the g-globin genes (HBG1 and HBG2). These findings link globin gene regulation with canonical hypoxia adaptation, provide a mechanism for HbF induction during increased erythropoietic demand (“stress erythropoiesis”), and suggest a new therapeutic approach for Sickle Cell Disease and β-Thalassemia.
Dr. Ann Dean will discuss the role of long non-coding RNAs (lncRNAs) in erythroid differentiation. LncRNAs are defined as RNA transcripts of longer than 200 nucleotides, without potential to code for a polypeptide. Nuclear lncRNAs have been found to regulate gene expression in almost all aspects, from transcription to translation, by diverse mechanisms. Dr. Dean will describe an antisense lncRNA transcribed opposite to the GATA2 gene that regulates numerous erythroid genes by interacting with erythroid transcription factors. She will also document a lncRNA transcribed from one of the enhancers of the Myb gene, an enhancer RNA or eRNA, that interacts with the co-regulator complex MLL1 to regulated Myb transcription. Loss of either of these lncRNAs results in elevated HBG1/HBG2 transcription, highlighting the potential of lncRNA manipulation as a therapeutic approach to Sickle Cell Disease and β-Thalassemia.
Dr. Gerd Blobel will summarize recent work that made use of advanced CRISPR screening tools to gain new insights into mechanisms that impinge on the switch from fetal to adult hemoglobin production in human erythroid cells. This includes new regulatory factors that act directly on the globin gene cluster as well as those that function via intermediates. Dr. Blobel will discuss the broader ramifications of this work with respect to fundamental mechanisms of developmental gene expression control and highlight the implications for new therapeutic approaches for the treatment of hemoglobinopathies.