Disease relevance of Locus Control Region

• Identification of a locus control region in the immunoglobulin heavy-chain locus that deregulates c-myc expression in plasmacytoma and Burkitt's lymphoma cells [1].
• Heme also promotes displacement of Bach1 from the beta-globin locus control region without affecting MafK binding in murine erythroleukemia cells [2].
• To overcome this problem, we investigated whether the HS4 chromatin insulator from the chicken beta-globin locus control region could protect a retrovirus vector from position effects [3].
• Advances have recently been made in the genetic correction of the hemoglobinopathies by means of lentiviral vectors and large locus control region (LCR) derivatives [4].
• Rhabdomyosarcoma arising in transgenic mice harboring the beta-globin locus control region fused with simian virus 40 large T antigen gene [5].

High impact information on Locus Control Region

• We show, in mice and humans, that a core ACH is developmentally conserved and consists of the hypersensitive sites (HS1-HS6) of the locus control region (LCR), the upstream 5' HS-60/-62 and downstream 3' HS1 [6].
• The five human beta-type-globin genes, epsilon, Ggamma, Agamma, delta and beta, are close together and are regulated by a locus control region (LCR) located at the 5' end of the locus [7].
• Expression of globin genes in developing erythroid cells is controlled by upstream locus control regions [8].
• Thus, the upstream DNA (previously named a dominant control or locus activation region, now denoted a locus control region) conferred the ability to express human beta-globin at high levels dependent on copy number on every mouse carrying the construct [9].
• As described in this issue of Immunity, Lee et al. have now used a transgenic mouse assay to identify a locus control region (LCR) that supports integration site-independent, copy number-dependent transcription of Il4 and Il13 [10].

Biological context of Locus Control Region

• We recently identified a 3' region of the rad50 gene possessing strong enhancer activity as well as activity consistent with function as a locus control region (LCR) for the flanking Th2 cytokine genes [11].
• In addition to local sequence elements the regulation of the high-level, development- and tissue-specific expression of the human beta globin gene cluster appears to require distant regulatory sequences which have been termed locus control region [12].
• Surprisingly, the beta-globin locus control region (LCR), although critical for high-level gene expression, plays little role in the overall architecture of the active locus [13].
• The beta-globin locus control region (LCR) confers high levels of position-independent, copy number-dependent expression onto globin transgenes [14].
• The 5'HS2 of the globin locus control region enhances transcription through the interaction of a multimeric complex binding at two functionally distinct NF-E2 binding sites [15].

Anatomical context of Locus Control Region

• In the chromatin of erythroid cells the locus control region is characterized by four DNaseI hypersensitive sites that are located 6-18 kb 5' of the epsilon globin gene [12].
• The beta SAD gene and the human alpha 2-globin gene, each linked to the beta-globin locus control region (LCR) were co-introduced into the mouse germ line [16].
• To achieve high expression levels of beta/delta-SCI1 in adult erythrocytes, the hybrid gene was placed under the transcriptional control of the human beta-globin promoter and the DNase I hypersensitive site 2 of the human beta locus control region [17].
• The function of the beta-globin locus control region (LCR) has been studied both in cell lines and in transgenic mice [18].
• We previously isolated an 87-kD nuclear protein from K562 cells that bound to DNA sequences in the beta-globin locus control region, gamma-globin promoter, and A gamma-globin enhancer [19].

Associations of Locus Control Region with chemical compounds

• To understand how this and other locus control region (LCR) elements contribute to high-level expression in erythroid cells, we have performed high-resolution, in vivo dimethyl sulfate footprinting [20].
• By contrast, acetylated H3 and H4 and H3 methylated at lysine 4 were enriched both at betamajor and at the upstream locus control region [21].
• Here, we describe transgenic mice that express C3 transferase under the control of the locus control region (LCR) of the CD2 gene; this regulatory element drives expression at a later stage of thymocyte development than the lck proximal promoter [7] [22].
• Also, deoxyribonuclease hypersensitive sites have been reported in and around these loci and were associated with an important locus control region for the GH/CS genes [23].
• We have produced two types of transgenic mice: first, mice expressing the transactivator rtTA chimeric protein under the control of mouse tyrosinase promoter and its locus control region (LCR), and; second, transgenic mice expressing a mouse tyrosinase cDNA construct driven by a minimal promoter inducible by rtTA in the presence of doxycycline [24].

Gene context of Locus Control Region

• The beta-globin locus control region (LCR) is a complex regulatory element that is essential for the appropriate red cell-specific expression of all cis-linked beta-globin genes [25].
• Deletion of RHS7 did not affect the expression of a linked Rad50 gene, but it did reduce long-range intrachromosomal interactions between the locus control region and promoters of the T(H)2 cytokine genes [26].
• Specification of unique Pit-1 activity in the hGH locus control region [27].
• The binding of the ubiquitous transcription factor Sp1 at the locus control region represses the expression of beta-like globin genes [28].
• These data suggest that the DNA regions flanking the mouse MT-I and MT-II genes have functions like the locus control regions described for other genes [29].

Analytical, diagnostic and therapeutic context of Locus Control Region

• Retroviral transfer of a human beta-globin/delta-globin hybrid gene linked to beta locus control region hypersensitive site 2 aimed at the gene therapy of sickle cell disease [17].
• An "in-out" strategy using gene targeting and FLP recombinase for the functional dissection of complex DNA regulatory elements: analysis of the beta-globin locus control region [30].
• Chromatin immunoprecipitation using anti-SATB1 anti-body shows selective binding in vivo in the beta-globin cluster to the hypersensitive site 2 (HS2) in the locus control region (LCR) and to the epsilon-globin promoter [31].
• Sequence analysis of the hypersensitive site cores of locus control region and of the genes coding for the transcription factors erythroid Kruppel-like factor and nuclear factor (erythroid-derived 2) were normal. beta-globin mRNA levels determined by real-time polymerase chain reaction were reduced in both types of beta-like carriers [32].

References