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Hox Genes
978
Housekeeping Gene
Housekeeping Gene
Hox Genes
M Goldman
A Gavalas and R Krumlauf
Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0639
Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0640
While different tissues in higher organisms are distinct phenotypically, they generally have the same set of genes. The phenotypic differences are brought about by differential regulation of gene expression. The genes that are expressed differentially are called `tissue-specific genes' (or sometimes `luxury genes'). Housekeeping genes, on the other hand, are expressed in all tissues, and are generally assumed to be involved in key steps in cellular metabolism such as DNA synthesis, protein synthesis, transcription, or energy metabolism. As there is a vast difference in how tissue-specific in contrast to housekeeping genes must be regulated, it is not surprising that the promoters of these genes differ as well. Most housekeeping genes utilize a promoter lacking the common TATA and CAAT boxes, and having instead a series of GC boxes (consensus sequence GGGCGG). GC boxes provide binding sites for the transcription factor Sp1 and, like the TATA box, direct the start of transcription. Since there are several GC boxes in the promoters of many housekeeping genes, the transcription start site is ambiguous. Indeed, many housekeeping gene transcripts have heterogeneous 50 start sites. The coding function of these genes is not impaired, however, because all of the alternative start sites are within the 50 untranslated region of the mRNA. As an example, the human c-Ha-ras oncogene promoter has about 80% GC content, 10 GC boxes, and at least four transcription start sites. The products of housekeeping genes may be needed in all cells, but in limited quantities. Therefore the housekeeping gene promoters are often weak, representing a baseline level of transcription. While some genes such as Hprt and Pgk fall squarely into the housekeeping category, as they are involved in nucleotide and energy metabolism, others are not so easily categorized. The metallothionein gene, for instance, is relatively quiescent, but is stimulated in the presence of heavy metals. This gene, however, is available for transcription in all cell types, even though it may not actually be transcribed at a particular point in time.
Hox genes are the homologs of the homeotic genes of the fruit fly Drosophila. The Drosophila homeotic genes were first identified through mutations that caused the transformation of a particular segment of the fly body into the likeness of another, hence the term homeotic from the Greek word homeo, which means similar. With the advent of molecular biology these genes were isolated and found to encode proteins that play fundamental roles in controlling regulation of many other genes. The Hox genes share a 60-amino-acid DNA-binding motif, the homeodomain, and in association with other homeodomain-containing proteins act as transcription factors to regulate gene expression. Today we know that these homeobox (Hox) genes have been widely conserved during metazoan evolution and they are present in organisms ranging from primitive chordates to humans. They are generally linked in chromosomal clusters. In simple ancestral organisms there is a single cluster. In association with genome-wide duplications in higher animals, this gave rise to the four Hox clusters that encompass a total of 39 Hox genes present in nearly all vertebrates, including mice and humans. A distinguishing hallmark of Hox clusters is the correlation between the physical arrangement of these genes along the chromosome and their temporal and spatial order of expression in the developing embryo. Genes located closer to the 30 end of the chromosomal clusters will be expressed earlier and in more anterior domains than genes located closer to their 50 ends. This property is known by the term temporal and spatial colinearity and is thought to reflect the mechanism that regulates the expression of these genes. Hox genes encode key developmental regulators, which specify the regional character of cells along the antero-posterior body axis of all three germ layers in both vertebrate and invertebrate embryos. Studies using the mouse and other vertebrates as model systems have shown that genetic mutations in some of the Hox genes or changes in their expression patterns result in abnormalities in a large number of tissues. This can cause defects in the nervous system, limbs, skeleton, and many organs. In some cases the defects are much milder than expected, but genetic studies have shown that some of these Hox genes
See also: Gene Regulation; TATA Box; Transcription
Housekeeping Gene
Housekeeping Gene
Hox Genes
M Goldman
A Gavalas and R Krumlauf
Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0639
Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0640
While different tissues in higher organisms are distinct phenotypically, they generally have the same set of genes. The phenotypic differences are brought about by differential regulation of gene expression. The genes that are expressed differentially are called `tissue-specific genes' (or sometimes `luxury genes'). Housekeeping genes, on the other hand, are expressed in all tissues, and are generally assumed to be involved in key steps in cellular metabolism such as DNA synthesis, protein synthesis, transcription, or energy metabolism. As there is a vast difference in how tissue-specific in contrast to housekeeping genes must be regulated, it is not surprising that the promoters of these genes differ as well. Most housekeeping genes utilize a promoter lacking the common TATA and CAAT boxes, and having instead a series of GC boxes (consensus sequence GGGCGG). GC boxes provide binding sites for the transcription factor Sp1 and, like the TATA box, direct the start of transcription. Since there are several GC boxes in the promoters of many housekeeping genes, the transcription start site is ambiguous. Indeed, many housekeeping gene transcripts have heterogeneous 50 start sites. The coding function of these genes is not impaired, however, because all of the alternative start sites are within the 50 untranslated region of the mRNA. As an example, the human c-Ha-ras oncogene promoter has about 80% GC content, 10 GC boxes, and at least four transcription start sites. The products of housekeeping genes may be needed in all cells, but in limited quantities. Therefore the housekeeping gene promoters are often weak, representing a baseline level of transcription. While some genes such as Hprt and Pgk fall squarely into the housekeeping category, as they are involved in nucleotide and energy metabolism, others are not so easily categorized. The metallothionein gene, for instance, is relatively quiescent, but is stimulated in the presence of heavy metals. This gene, however, is available for transcription in all cell types, even though it may not actually be transcribed at a particular point in time.
Hox genes are the homologs of the homeotic genes of the fruit fly Drosophila. The Drosophila homeotic genes were first identified through mutations that caused the transformation of a particular segment of the fly body into the likeness of another, hence the term homeotic from the Greek word homeo, which means similar. With the advent of molecular biology these genes were isolated and found to encode proteins that play fundamental roles in controlling regulation of many other genes. The Hox genes share a 60-amino-acid DNA-binding motif, the homeodomain, and in association with other homeodomain-containing proteins act as transcription factors to regulate gene expression. Today we know that these homeobox (Hox) genes have been widely conserved during metazoan evolution and they are present in organisms ranging from primitive chordates to humans. They are generally linked in chromosomal clusters. In simple ancestral organisms there is a single cluster. In association with genome-wide duplications in higher animals, this gave rise to the four Hox clusters that encompass a total of 39 Hox genes present in nearly all vertebrates, including mice and humans. A distinguishing hallmark of Hox clusters is the correlation between the physical arrangement of these genes along the chromosome and their temporal and spatial order of expression in the developing embryo. Genes located closer to the 30 end of the chromosomal clusters will be expressed earlier and in more anterior domains than genes located closer to their 50 ends. This property is known by the term temporal and spatial colinearity and is thought to reflect the mechanism that regulates the expression of these genes. Hox genes encode key developmental regulators, which specify the regional character of cells along the antero-posterior body axis of all three germ layers in both vertebrate and invertebrate embryos. Studies using the mouse and other vertebrates as model systems have shown that genetic mutations in some of the Hox genes or changes in their expression patterns result in abnormalities in a large number of tissues. This can cause defects in the nervous system, limbs, skeleton, and many organs. In some cases the defects are much milder than expected, but genetic studies have shown that some of these Hox genes
See also: Gene Regulation; TATA Box; Transcription