Sickle cell disease (SCD) is one of the most common hemoglobinopathies worldwide. It is caused by a homozygous mutation in codon 6 of the beta globin gene (HBB), which leads to polymerization of the variant hemoglobin and sickled red blood cells that obstruct blood vessels and reduce oxygen delivery to tissues. Patients with SCD have multiple clinical problems, including pain crises, anemia and organ damage. However, not all patients with SCD display all these clinical manifestations. One major factor for reduced occurrences of symptoms is fetal hemoglobin (HbF). HbF is the main hemoglobin in the fetus, and declines one year after birth to less than one percent of total hemoglobin. Nevertheless, there are individuals who continue to have high levels of HbF into adulthood, which is beneficial for an individual with SCD because HbF reduces the amount of sickle polymer in red blood cells. There are three major quantitative trait loci (QTL) associated with high HbF. However, these QTL account for 20-45% of HbF variance. Therefore, further investigation is required to fully understand how HbF is regulated.
The HBS1L-MYB intergenic polymorphism (HMIP) on chromosome 6q23 is one of the major QTL associated with high HbF. This region is also known to regulate other erythroid-specific traits due to an enhancer element that promotes the expression of the downstream gene, MYB, which controls hemoglobin expression and erythroid proliferation and maturation. The presence of RNA polymerase II binding and a 50-bp transcript suggested that a long noncoding RNA (lncRNA) is transcribed from this region. LncRNAs are non-protein-coding transcripts greater than 200 nucleotides and are involved in gene regulation. Therefore, it was hypothesized that a lncRNA is transcribed from the enhancer of MYB and regulates hemoglobin expression.
I characterized a novel lncRNA, 1283 bp in length that was differentially expressed among various tissue types, among erythroid progenitor cells with different hemoglobin makeup, and also during erythroid differentiation. Furthermore, knockdown of this lncRNA, named the HBS1L-MYB intergenic long noncoding RNA (HMI-LNCRNA), significantly increased HbF. Taken together, these observations suggest that HMI-LNCRNA can be a possible therapeutic target to increase HbF expression in patients with SCD and β-thalassemia. / 2018-05-01T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/26513 |
| Date | 01 November 2017 |
| Creators | Morrison, Tasha Alease |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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