Cμ-containing transcripts initiate heterogeneously within the IgH enhancer region and contain a novel 5′-nontranslatable exon

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Abstract
Transcriptional competence of the immunoglobulin heavy-chain locus (IgH) is established at an early stage of lymphoid cell development, leading to the appearance of RNA components, previously called Cμ RNA1 or sterile-μ RNA2, which contain constant-region sequences but lack variable-region sequences. These components are of two types: those which initiate in the D region of alleles that have undergone DJH (diversity–joining region) rearrangement (Dμ transcripts) and those which initiate within the JH–Cμ intron (hereafter termed Iμ transcripts)3,4. In pre-B and early B cells, Dμ and lμ transcripts are nearly as abundant as the messenger RNA encoding μ heavy chain2,3,5. The Dμ transcripts are spliced into RNAs containing D, JH and Cμ sequences, and in some, but not all, cases these RNAs are translated into Dμ proteins4. To establish whether the Iμ transcripts have any translational potential and to elucidate the structure of their promoter region, we have determined their transcription initiation sites and their mode of splicing. As reported here, by using sequence analysis of cloned Iμ complementary DNAs, primer extension and S1, nuclease mapping, we have found that these transcripts have remarkable 5′ heterogeneity: ther e are more than five distinct start sites spanning a region of 44 nucleotides that is located downstream of an octanucleotide found in all variable-region promoters. Such imprecise initiation may result from the lack of a well-defined T A T AA motif and the unusual proximity of the octanucleotide to the enhancer region. Approximately 700 nucleotides downstream from these initiation sites, a cryptic splice site is used to create a nontranslatable exon (‘nontron’) which is joined to the Cμ1 domain. The properties of the nontron may be important for the mechanism of allelic exclusion.