Abstract
The myelin basic protein (MBP) gene is expressed only in oligodendrocytes and Schwann cells, and expression follows a tightly regulated developmental time course. Cell type- and developmental stage-specific expression of the MBP gene appears to be regulated by a series of cis-acting elements located upstream of the transcription start site. The proximal element of the MBP regulatory region (MB1), located between nucleotides -14 and -50, is one of several elements participating in the programmed expression of MBP. In this report, we describe the molecular cloning and characterization of myelin gene expression factor-2 (Myef-2), a protein isolated from mouse brain that binds specifically to single-stranded DNA derived from the MB1 element and represses transcription of the MBP gene in transient transfection assay. Myef-2 mRNA is developmentally regulated in mouse brain; its peak expression occurs at postnatal day 7, prior to the onset of MBP expression. The developmental pattern of Myef-2 mRNA expression coincides with that previously described for SCIP, a POU domain transcription factor that also represses myelin basic protein expression. The myef-2 gene maps to mouse chromosome 2. The relevance of these findings for regulation of MBP gene expression and oligodendrocyte differentiation is discussed.
Highlights
5534; Fax: 215-923-8021. 1 The abbreviations used are: MBP, myelin basic protein; MyEF-2, myelin gene expression factor-2; kb, kilobase(s);CMV, cytomegalovirus; restriction fragment length polymorphisms (RFLPs), restriction fragment length polymorphism; bp, base pairrs); CAT, chloramphenicol acetyltransferase; RRM,RNA recognition motif; hnRNP M4, heterogeneous ribonucleoprotein M4; IPTG, isopropyl-lthio-{3-D-galactopyranoside
It has long been assumed that promoter and enhancer binding factors recognize their cognate sites on duplex DNA [4, 16], some transcription factors have the capacity to bind in a sequence-specific manner to single-stranded DNA
We have investigated the potential role of sequence-specific single-stranded DNA binding proteins in mediating the transcriptional activity of MBP through the MBI element
Summary
5534; Fax: 215-923-8021. 1 The abbreviations used are: MBP, myelin basic protein; MyEF-2, myelin gene expression factor-2; kb, kilobase(s);CMV, cytomegalovirus; RFLP, restriction fragment length polymorphism; bp, base pairrs); CAT, chloramphenicol acetyltransferase; RRM,RNA recognition motif; hnRNP M4, heterogeneous ribonucleoprotein M4; IPTG, isopropyl-lthio-{3-D-galactopyranoside. The myogenic determination factor MyoD has been shown to bind to the muscle-specific enhancer of the mouse creatine kinase M gene, whether the element is presented in duplex or single-stranded form [17]. Other novel transcription factors have been identified that possess sequence-specific single-stranded DNA binding activity, interacting with elements in a number of muscle-specific genes [17, 20] and in the regulatory region of the human neurotropic JC virus [21]. As first demonstrated by Weintraub and Groudine [22], the enzyme DNase I preferentially digests genes that are transcriptionally active In this respect, analysis of the chicken adult l3-globin gene indicates that its 5' -flanking region is highly sensitive to cleavage by nuclease SI [23] and by bromoacetaldehyde [24], suggesting that this pro-
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