The Chicken Lysozyme Locus as a Paradigm for the Complex Developmental Regulation of Eukaryotic Gene Loci (1997)

Gene loci of higher organisms have complex structural features. In some cases their coding regions occupy many, even hundreds, of kilobases of DNA. Additionally, the sequences that contain the information for the correct spatial and temporal regulation of a particular gene locus during development often exceed the extensions of the coding region by severalfold. The question of what type of information is encoded in these vast amounts of DNA has puzzled researchers from the beginning.It is now clear that eukaryotic genes are regulated by a number of different cis-regulatory elements distributed over large distances. A convenient way to assay the number and the distribution of cis-regulatory elements has been the mapping of DHS 1The abbreviations used are: DHS, DNase I-hypersensitive chromatin site(s); kb, kilobase(s); LCR, locus control region; MNase, micrococcal nuclease. 1The abbreviations used are: DHS, DNase I-hypersensitive chromatin site(s); kb, kilobase(s); LCR, locus control region; MNase, micrococcal nuclease. in chromatin. Such local chromatin perturbations are in most cases caused by the binding of transcription factors to their cognate DNA sequences. The pattern of DHS can undergo dramatic developmental changes, indicating a change in the activity of cis-regulatory elements. In addition, the analysis of protein-DNA interactions at a single-nucleotide resolution levelin vivo has demonstrated that, depending on the developmental stage, different combinations of transcription factors can occupy the same cis-regulatory element (1Roque M.C. Smith P.A. Blasquez V.C. Mol. Cell. Biol. 1996; 16: 3138-3155Crossref PubMed Google Scholar, 2Gualdi R. Bossard P. Zheng M. Hamada Y. Coleman J.R. Zaret K.S. Genes Dev. 1996; 10: 1670-1682Crossref PubMed Scopus (462) Google Scholar). These experiments indicate that the transcriptional activation of a gene locus is achieved by the cooperation of several different cis-regulatory elements, which, in turn, assemble transcription factors in a sequential, developmentally controlled fashion. However, the assembly of active transcription factor complexes on natural genes does not occur on naked DNA but in a chromatin context, where nucleosome-DNA interactions have to be counteracted. Hence, the activation of a gene locus requires at least the following steps: the perturbation of chromatin structure by the binding of transcription factors on cis-regulatory elements, the developmentally controlled reorganization of transcription factor complexes, the assembly of the basal transcription machinery and its elements, the of in the of active transcriptional during of DNA can the of locus activation be the basal of cis-regulatory elements of particular gene loci can be by and the of activation of a gene locus from the can be in a in The locus be the of cis-regulatory elements the of and be on the In addition, to the of different cis-regulatory elements in the developmental control of gene locus be to the of a chromatin structure the transcriptional activity of the on the of the transcriptional activation of the a for developmentally regulated eukaryotic gene the of gene is in the and in of the of the M.C. Biol. PubMed Google Scholar, M. PubMed Scopus Google Scholar). In the gene is during the of to and M. The of Scholar, M.C. DNA Biol. PubMed Scopus Google Scholar). The structural of the locus are by DNase of chromatin over of the region PubMed Scopus Google Scholar). DHS and cis-regulatory elements are chromatin M. The of Scholar, M.C. DNA Biol. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, M. PubMed Scopus Google Scholar). analysis kb, kb, and a element a element and a complex M. and in and Cell. PubMed Scopus Google and The of the DNase sequences binding to the in PubMed Scopus Google that the locus a Biol. PubMed Scopus Google Scholar). However, at is these sequences are to the in vivo 1996; Google in demonstrated that the gene locus is in the type and is by M. PubMed Scopus Google Scholar). 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Genes Dev. 1996; 10: PubMed Scopus Google Scholar). a where several cis-regulatory elements have to that the of the of transcription factor complexes on a gene locus is for its In the of the locus that region is to the to transcriptional activity and active chromatin structure at cis-regulatory elements are experiments the of gene locus activation in development have a of In to of chromatin in is on of spatial is often a change in the these are at the different that control gene that is information to where have been and have is for correct pattern In the same the of chromatin structure reorganization during the be for correct gene locus is the of experiments the of gene Gene loci of higher organisms have complex structural features. In some cases their coding regions occupy many, even hundreds, of kilobases of DNA. Additionally, the sequences that contain the information for the correct spatial and temporal regulation of a particular gene locus during development often exceed the extensions of the coding region by severalfold. The question of what type of information is encoded in these vast amounts of DNA has puzzled researchers from the is now clear that eukaryotic genes are regulated by a number of different cis-regulatory elements distributed over large distances. A convenient way to assay the number and the distribution of cis-regulatory elements has been the mapping of DHS 1The abbreviations used are: DHS, DNase I-hypersensitive chromatin site(s); kb, kilobase(s); LCR, locus control region; MNase, micrococcal nuclease. 1The abbreviations used are: DHS, DNase I-hypersensitive chromatin site(s); kb, kilobase(s); LCR, locus control region; MNase, micrococcal nuclease. in chromatin. Such local chromatin perturbations are in most cases caused by the binding of transcription factors to their cognate DNA sequences. The pattern of DHS can undergo dramatic developmental changes, indicating a change in the activity of cis-regulatory elements. In addition, the analysis of protein-DNA interactions at a single-nucleotide resolution levelin vivo has demonstrated that, depending on the developmental stage, different combinations of transcription factors can occupy the same cis-regulatory element (1Roque M.C. Smith P.A. Blasquez V.C. Mol. Cell. Biol. 1996; 16: 3138-3155Crossref PubMed Google Scholar, 2Gualdi R. Bossard P. Zheng M. Hamada Y. Coleman J.R. Zaret K.S. Genes Dev. 1996; 10: 1670-1682Crossref PubMed Scopus (462) Google Scholar). These experiments indicate that the transcriptional activation of a gene locus is achieved by the cooperation of several different cis-regulatory elements, which, in turn, assemble transcription factors in a sequential, developmentally controlled fashion. However, the assembly of active transcription factor complexes on natural genes does not occur on naked DNA but in a chromatin context, where nucleosome-DNA interactions have to be counteracted. Hence, the activation of a gene locus requires at least the following steps: the perturbation of chromatin structure by the binding of transcription factors on cis-regulatory elements, the developmentally controlled reorganization of transcription factor complexes, the assembly of the basal transcription machinery and its elements, the of in the of active transcriptional during of DNA can the of locus activation be the basal of cis-regulatory elements of particular gene loci can be by and the of activation of a gene locus from the can be in a in The locus be the of cis-regulatory elements the of and be on the In addition, to the of different cis-regulatory elements in the developmental control of gene locus be to the of a chromatin structure the transcriptional activity of the on the of the transcriptional activation of the a for developmentally regulated eukaryotic gene The the of gene is in the and in of the of the M.C. Biol. PubMed Google Scholar, M. PubMed Scopus Google Scholar). In the gene is during the of to and M. The of Scholar, M.C. DNA Biol. PubMed Scopus Google Scholar). The structural of the locus are by DNase of chromatin over of the region PubMed Scopus Google Scholar). DHS and cis-regulatory elements are chromatin M. The of Scholar, M.C. DNA Biol. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, M. PubMed Scopus Google Scholar). analysis kb, kb, and a element a element and a complex M. and in and Cell. PubMed Scopus Google and The of the DNase sequences binding to the in PubMed Scopus Google that the locus a Biol. PubMed Scopus Google Scholar). However, at is these sequences are to the in vivo 1996; Google in demonstrated that the gene locus is in the type and is by M. PubMed Scopus Google Scholar). The of the different cis-regulatory elements to transcriptional activation of the gene locus by PubMed Scopus Google Scholar). a of region However, of is cis-regulatory region is for correct locus activation in development the of cis-regulatory elements is the of the their does not of region in is is a higher of the of The that a gene locus is has been used to for the structural and extensions not by large the of PubMed Scopus Google Scholar, R. PubMed Scopus Google Scholar). The gene is in the and in of the of the M.C. Biol. PubMed Google Scholar, M. PubMed Scopus Google Scholar). In the gene is during the of to and M. The of Scholar, M.C. DNA Biol. PubMed Scopus Google Scholar). The structural of the locus are by DNase of chromatin over of the region PubMed Scopus Google Scholar). DHS and cis-regulatory elements are chromatin M. The of Scholar, M.C. DNA Biol. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, M. PubMed Scopus Google Scholar). analysis kb, kb, and a element a element and a complex M. and in and Cell. PubMed Scopus Google and The of the DNase sequences binding to the in PubMed Scopus Google that the locus a Biol. PubMed Scopus Google Scholar). However, at is these sequences are to the in vivo 1996; Google Scholar). in demonstrated that the gene locus is in the type and is by M. PubMed Scopus Google Scholar). The of the different cis-regulatory elements to transcriptional activation of the gene locus by PubMed Scopus Google Scholar). a of region However, of is cis-regulatory region is for correct locus activation in development the of cis-regulatory elements is the of the their does not of region in is is a higher of the of The that a gene locus is has been used to for the structural and extensions not by large the of PubMed Scopus Google Scholar, R. PubMed Scopus Google Scholar). The of in Gene question now to a gene locus is a of cis-regulatory elements, which, in turn, are by of binding by DNA sequences is to the interactions the cis-regulatory elements and does chromatin structure in the chromatin structure of the locus in the structural reorganization of the cis-regulatory elements at different developmental M.C. DNA Biol. PubMed Scopus Google Scholar). that the chromatin of the locus is in several depending on the of the The gene in is and the chromatin for the DHS at the is the DHS at the the and at the the DHS at and a DHS at the is activity from a in to a higher activity in These experiments a transcriptional of the gene where are active and where the element has been used to for in the region of the In the are at most cis-regulatory elements M.C. 1996; PubMed Scopus Google in cis-regulatory element a structural transcription to activation in of chromatin which, are of different in different cis-regulatory elements. the a pattern of the of gene activation a perturbation of The same is at the In in the of the Zaret Cell. PubMed Scopus Google to be the activation of the The is even at the to be in the of a DHS at the indicating that transcription factor assembly on their to what is at the M. M. 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PubMed Scopus Google transcription factors binding to binding on elements of natural gene loci have to on binding on sequences. elements be to the large to the and to a gene locus the active The question now to a gene locus is a of cis-regulatory elements, which, in turn, are by of binding by DNA sequences is to the interactions the cis-regulatory elements and does chromatin structure in the chromatin structure of the locus in the structural reorganization of the cis-regulatory elements at different developmental M.C. DNA Biol. PubMed Scopus Google Scholar). that the chromatin of the locus is in several depending on the of the The gene in is and the chromatin for the DHS at the is the DHS at the the and at the the DHS at and a DHS at the is activity from a in to a higher activity in These experiments a transcriptional of the gene where are active and where the element has been used to for in the region of the In the are at most cis-regulatory elements M.C. 1996; PubMed Scopus Google in cis-regulatory element a structural transcription to activation in of chromatin which, are of different in different cis-regulatory elements. the a pattern of the of gene activation a perturbation of The same is at the In in the of the Zaret Cell. PubMed Scopus Google to be the activation of the The is even at the to be in the of a DHS at the indicating that transcription factor assembly on their to what is at the M. M. PubMed Scopus Google Scholar). 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