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Transcriptionally Regulatory Sequences of Phylogenetic Significance
Published in S. K. Dutta, DNA Systematics, 2019
In a eukaryotic cell, transcriptionally active chromatin is more sensitive toward DNase I than inactive chromatin. The hypersensitive site has been located at the regulatory region preceding the coding sequence of several structural genes.264–270 The sensitivity is conferred by chromosomal protein(s) that is associated with DNA instead of the sequence of DNA itself. Tissue-specific patterns of DNase I sensitivity have been demonstrated for genes coding for chicken β-globin, chicken lysozyme, Drosophila heat shock proteins, histones, and rat preproinsulin.
The Structural and Functional Roles of Specific Nonhistone Protein Fractions in Chromatin
Published in Isaac Bekhor, Carol J. Mirell, C. C. Liew, Progress in Nonhistone Protein Research, 1985
As mentioned previously, differential gene expression appears to be correlated with alterations in chromatin structure as revealed by preferential sensitivity to DNase I of active transcribed tissue-specific genes.11,17,102,12 Detailed analysis of DNase I digestion of transcribed genes has revealed discrete sites that are extremely sensitive to DNase I clustered at or near the 5’-ends of the genes, suggesting an especially exposed chromatin structure at the 5’-terminus.102,103,105–110 There is also an overall DNase I sensitivity that extends throughout the transcription unit. Investigation of the components necessary to establish and maintain the DNase I hypersensitive site, which appears to be a chromatin structure with a regulatory function, may provide an understanding of the mechanism of chromatin transcription and consequently the mechanism of neoplastic transformation. Hyperacetylation of histones appear to be correlated with increased transcriptional activity.111,112 The nonhistone proteins HMG-14 and -17 have also been shown to play roles in the maintenance of DNase I sensitivity of transcribed sequences in chromatin.23,24,113,12 As neither of these chromatin components exhibit tissue specificity, it has been surmised that other components exist that are responsible for conferring selective active chromatin structural alterations.9,24,115
Regulation of C-Reactive Protein, Haptoglobin, and Hemopexin Gene Expression
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Dipak P. Ramji, Riccardo Cortese, Gennaro Ciliberto
DNase-I-hypersensitive sites (DHSs) reflect changes in the conformational structure of the chromatin in response to the interaction of regulatory trans-acting factors with their target sequences.55 In order to identify putative regions involved in the control of CRP expression, the DHSs within and adjacent to the CRP gene were mapped in both uninduced and induced transgenic mice.53 In uninduced liver, a constitutive and tissue-specific DHS was identified in the 3′ flanking sequence downstream from the polyadenylation site. This region is probably involved in developmental control of CRP expression, a conclusion supported by the observation that transgenic mice obtained with CRP constructs carrying a deletion of this DNA region do not express the transgene.53 The inflammatory stimulus LPS induces the appearance of three closely spaced, liver-specific DHSs. Two of these map around the CAP site and −250 bp, and the third one is located approximately 600 bp upstream.53 More recent work with transgenic mice has resulted in a better definition of the sequences involved in both liver-specific and inducible expression.56 Several segments of the original construct were tested either alone or in various combinations. The conclusion of this study is that correct regulation requires a cooperation of signals located in the immediate 5′ and 3′ flanking sequence of the gene (which includes the DHSs previously mapped), and a 2-kb region containing the CRP pseudogene,57 which is located 6 to 8 kb downstream from the CRP gene.56 The role of this last region is to ensure a consistently low background level of expression in noninduced mice and a high degree of inducibility.
Novel α0-Thalassemia Deletion Identified in an Indian Infant with Hb H Disease
Published in Hemoglobin, 2020
Jordyn A. Moore, Beverley M. Pullon, Kylie M. Drake, Stephen O. Brennan
α-Thalassemia (α-thal) is one of the most commonly inherited single-gene disorders and is prevalent in the Mediterranean, Middle East, Africa, Southeast Asia and Indian subcontinent [1]. The disorder is characterized by reduced α-globin synthesis and is associated with defects of the α-globin gene cluster located on chromosome 16 (16p13.3) [1]. The major regulatory element [hypersensitive site-40 (HS-40)] is positioned near the telomere, upstream of the embryonic ζ-(HBZ), Ψ- (pseudo), minor globin-like, adult (HBA2 and HBA1) and θ- (HBQ1) globin genes [2,3]. Deletion or point mutation of the α-globin gene cluster can cause α-thal. However, the vast majority of mutations described to date involve the deletion of HBA2 and HBA1; functional genes responsible for α-globin production [2,3].
GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy
Published in Expert Review of Hematology, 2018
Te Ling, John D. Crispino, Maria Zingariello, Fabrizio Martelli, Anna Rita Migliaccio
The strong structural similarity among proteins of the GATA family makes the strict requirement for GATA1 in erythroid and megakaryocyte lineage development surprising. To explain this paradox, it was hypothesized that, by contrast with other transcription factors, the lineage specific functions of the GATA family members depend on a tight regulation of their expression rather than on their protein structure. This hypothesis was first tested by the Philipsen laboratory, which demonstrated that the embryonically lethal phenotype induced by the Gata1null mutation in mice is rescued by forced expression of either Gata1, 2, or 3 provided that they are expressed in the appropriate spatiotemporal pattern [54]. This hypothesis was further tested by additional studies that aimed to identify the lineage-specific enhancers of Gata1. Proof for the existence of these regions was first provided by Nicolis et al. [55] The regions were then refined by additional studies by the Yamamoto and Orkin laboratories which pioneered the use of knockdown mutations, that is, deletion of regulatory regions which reduce mRNA translation, to identify lineage-specific enhancers. These studies revealed that Gata1 contains three main hypersensitive sites which were marked as hypersensitive site (HS) HS1, 2, and 3, with HS1 being the enhancer that primarily drives erythroid and megakaryocytic-specific expression [56–58].
Sickle cell disease in the era of precision medicine: looking to the future
Published in Expert Review of Precision Medicine and Drug Development, 2019
Martin H Steinberg, Sara Kumar, George J. Murphy, Kim Vanuytsel
Other cis-acting elements with putative roles in HbF gene expression were located within the HBD-HBG1 intergenic region, in the HBB LCR hypersensitive site-2 core, ~530 bp 5ʹ to HBB and in the olfactory gene cluster upstream of the LCR. An additional candidate region was a 3.5 kb element near the 5ʹ portion of HBD but this site is devoid of BCL11A binding sites. Regions remote from the HbF genes are less likely to have major roles in switching from fetal to embryonic to adult hemoglobins.