Hox cluster polarity in early transcriptional availability: a high order regulatory level of clustered Hox genes in the mouse

The molecular mechanism underlying the 3' to 5' polarity of induction of mouse Hox genes is still elusive. While relief from a cluster-encompassing repression was shown to lead to all Hoxd genes being expressed like the 3'most of them, Hoxd1 (Kondo and Duboule, 1999), the molecular ba...

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Bibliographic Details
Published in:Mechanisms of development 2002-11, Vol.119 (1), p.81-90
Main Authors: Roelen, Bernard A J, de Graaff, Wim, Forlani, Sylvie, Deschamps, Jacqueline
Format: Article
Language:English
Subjects:
Animals
Chromatin - metabolism
Galactosides
Gene Expression Regulation, Developmental
Homeodomain Proteins - metabolism
In Situ Hybridization
Indoles
Lac Operon
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
RNA, Messenger - metabolism
Time Factors
Transcription Factors - metabolism
Transcription, Genetic
Transgenes
Tretinoin - pharmacology
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Summary:The molecular mechanism underlying the 3' to 5' polarity of induction of mouse Hox genes is still elusive. While relief from a cluster-encompassing repression was shown to lead to all Hoxd genes being expressed like the 3'most of them, Hoxd1 (Kondo and Duboule, 1999), the molecular basis of initial activation of this 3'most gene, is not understood yet. We show that, already before primitive streak formation, prior to initial expression of the first Hox gene, a dramatic transcriptional stimulation of the 3'most genes, Hoxb1 and Hoxb2, is observed upon a short pulse of exogenous retinoic acid (RA), whereas it is not in the case for more 5', cluster-internal, RA-responsive Hoxb genes. In contrast, the RA-responding Hoxb1lacZ transgene that faithfully mimics the endogenous gene (Marshall et al., 1994) did not exhibit the sensitivity of Hoxb1 to precocious activation. We conclude that polarity in initial activation of Hoxb genes reflects a greater availability of 3'Hox genes for transcription, suggesting a pre-existing (susceptibility to) opening of the chromatin structure at the 3' extremity of the cluster. We discuss the data in the context of prevailing models involving differential chromatin opening in the directionality of clustered Hox gene transcription, and regarding the importance of the cluster context for correct timing of initial Hox gene expression.Interestingly, Cdx1 manifested the same early transcriptional availability as Hoxb1.
ISSN:0925-4773
DOI:10.1016/S0925-4773(02)00329-5