Studies on the structure and expression of the human CD4 gene.

Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.

Studies on the structure and expression of the human CD4 gene.

Diss Abstr Int [B]; 52(7):3393 1992. Unique Identifier : AIDSLINE ICDB/93682486
Wong GT; Cornell Univ. Medical Center

Abstract: The human CD4 protein is a 55-kD glycoprotein predominantly expressed on the cell surface of thymocytes and T-cells. CD4 functions in these cells to increase the affinity of a T-cell receptor (TcR) for antigen bound to major histocompatibility complex (MHC) class II proteins. CD4 also acts as a coreceptor, complexing transiently with the TcR during activation, and recruiting to the TcR the src-like protein tyrosine kinase p56lck. CD4 may play a direct role in thymocyte differentiation; its expression on early thymocytes may be critical for regulating thymocyte expression of MHC class-restricted TcR. Human CD4 is also the only known receptor for the human immunodeficiency virus. Correct functioning of the CD4 protein relies on the appropriate expression of the CD4 gene. This thesis probes the nature of the regulatory mechanisms required for cell-type-specific expression of CD4. Initially, we determined the structure of the human CD4 gene in relation to its transcriptional unit. We defined the 5' and 3' ends of transcription and determined that the human CD4 gene spans more than 60 kb. This information allowed the construction of a human CD4 mini-gene, CD4.1, which we introduced into transgenic mice to test for the presence or absence of cis-acting regulatory sequences required for cell-type specific expression. We observed that CD4.1 expressed at high levels in B-cells and macrophages, not in thymocytes and T-cells. We concluded that CD4.1 included the cis-acting sequences required for B-cell and macrophage expression but not sequences required for high-levels of thymocyte and T-cell expression. To identify regions of the human CD4 locus which may contain cis-acting sequence elements required for high level T-cell expression, we initiated a series of mapping experiments to identify DNase I hypersensitive (HS) sites in human CD4 chromatin. HS sites often distinguish transcriptionally active genes from inactive genes, and are thought to be hallmarks of transcriptional regulatory sequences. We were able to show that the 5' end of the human CD4 gene contains many HS regions. Consistent with the observed expression of CD4.1, we defined a macrophage-specific DNase I hypersensitive site, which maps to a region of the human CD4 gene included in CD4.1. Two additional HS sites, distal to the 5' border of CD4.1, are observed in chromatin of T-cells. Moreover, one of these sites is specific for CD4+ T-cells. Finally, we presented evidence of T-cell specific- and CD4+ T-cell specific-DNase I hypersensitive sites which map further distal to the transcriptional unit than those regions included in CD4.1. We propose, based on these experiments, that T-cell-specific transcriptional regulatory elements may be encoded in these HS regions, and may be responsible for high levels of human CD4 gene expression in T-cells. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD91-35436).

Keywords: Antigens, CD4/*GENETICS/METABOLISM Deoxyribonucleases, Type I Site-Specific/METABOLISM Gene Expression Gene Expression Regulation Histocompatibility Antigens Class II Human Receptors, Antigen, T-Cell T-Lymphocytes/PHYSIOLOGY Thymus Gland/CYTOLOGY Transcription Factors THESIS
930228
M9320870

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