Locus control region

The locus control region (LCR) is a genetic control region that controls the activity of a gene region. LCRs are called DNase-sensitive regions. These are assumed to have an "open" chromatin structure. In this "open" chromatin structure, the DNA is cleared of histones so that transcription factors can bind to this DNA region.

The concept of locus control regions is based on the observation that the tissue-specific regulation of gene expression during embryonic development as well as in the adult organism is not only based on regulatory elements close to the nucleus (such as promoter, enhancer, silencer), but also on interactions with regulatory elements located further away on the same chromosome.

Locus control regions increase the expression of whole gene clusters in a cell-typical way. In addition to binding sites for transcription factors, they obviously also have an influence on the chromatin structure in the corresponding region.

Promoter regions are located towards the 5'-end in front of the gene. RNA polymerases bind to these sites to catalyze gene transcription.

Enhancer regions are located either in front or behind the gene. They are important for the tissue-specific regulation of protein gene expression and the regulation of the synthesis of the different protein chains.

LRCs as important control elements of gene expression can be located many thousands of base pairs away from the actual site of transcription. How these large distances within the genome are bridged is still hypothetical. Ultimately, various models are being discussed:

• Loop formation or "looping model". The LCR sequence of the DNA forms a loop that physically approaches the gene region that is to be transcribed. This physical approximation allows the LCR sequence to influence the transcription of the gene.
• Along-strand method: In the so-called "along-strand method", the complex of LCR and bound factors travels along the DNA until it recognizes the corresponding promoter region.

LCRs are particularly well described in the beta-globulin gene group.

Another example is the human growth hormone (hGH) cluster, which comprises five highly conserved genes (Chen et al. 1989). hGH-N is specifically expressed in somatotroph cells of the pituitary gland, whereas the expression of hCS-L, hCS-A, hGH-V and hCS-B is restricted to syncytiotrophoblasts of the placenta. This cluster is controlled by a distant LCR (hGH LCR) comprising five DNase I HS located -14.5 to -32 kb 5′ to the hGH-N gene. The closely linked HSI and HSII are pituitary-specific, HSIV is placenta-specific, and HSIII and HSV are present in both tissues (Elefant et al., 2000). Site-specific inactivation of HSI leads to loss of acetylation in this domain, loss of critical transfactor occupancy at the hGH-N promoter and a 20-fold reduction in hGH-N expression (Ho Y et al. 2002). Thus, HSI plays an essential role in the establishment of the acetylated domain and in the activation of hGH-N transcription in the pituitary gland.

However, LCRs are not limited to this group of genes. In humans, it is estimated that there are around 1500 - 2000 gene families whose gene activities are controlled by LCRs. Other examples are the cytochome P450 genes, the family of receptor genes, the kinesin genes, globin genes or immunoglobulin genes.

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