Abstract
An elucidation of the key regulatory factors in pancreas development is critical for understanding the pathogenesis of diabetes mellitus. This study examined whether a specific regulatory mechanism that exists in neuronal development also plays a role in the pancreas. In non-neuronal cells, neuron-restrictive silencer factor (NSRF) actively represses gene transcription via a sequence-specific DNA motif known as the neuron-restrictive silencer element (NRSE). This DNA motif has been identified in many genes that are specific markers for cells of neuronal and neuroendocrine lineage. We identified several genes involved in pancreas development that also harbor NRSE-like motifs, including pdx-1, Beta2/NeuroD, and pax4. The paired homeodomain transcription factor Pax4 is implicated in the differentiation of the insulin-producing beta-cell lineage because disruption of the pax4 gene results in a severe deficiency of beta-cells and the manifestation of diabetes mellitus in mice. The NRSE-like motif identified in the upstream pax4 promoter is highly conserved throughout evolution, forms a DNA-protein complex with NRSF, and confers NRSF-dependent transcriptional repression in the context of a surrogate gene promoter. This cis-activating NRSE element also confers NRSF-dependent modulation in the context of the native pax4 gene promoter. Together with earlier reports, these new findings suggest an important functional role for NRSF in the expression of the pax4 gene and infer a role for NRSF in pancreatic islet development.
Highlights
The cis-regulatory neuron-restrictive silencer element (NRSE) is a 21-bp motif that confers transcriptional repression of genes in many non-neuronal cell types [2, 3]
We show that NRSF binds to the NRSE-like motif in the 5Ј-regulatory region of the pax4 gene and that it confers significant NRSF-mediated repression of gene transcription in the context of a constitutively active promoter
The NRSE displays cis-regulatory control of transcription in the context of the native pax4 gene promoter region in a clonal pancreatic -cell line. These findings suggest that NRSF may be a relevant regulatory factor in pax4 gene expression and may, in turn, be important in -cell differentiation
Summary
The cis-regulatory NRSE is a 21-bp motif that confers transcriptional repression of genes in many non-neuronal cell types [2, 3]. In non-neuronal cells, neuron-restrictive silencer factor (NSRF) actively represses gene transcription via a sequence-specific DNA motif known as the neuron-restrictive silencer element (NRSE). We investigated whether the NRSE/NRSF1 transcriptional repressor mechanism is involved in islet cell gene expression coincident with its role in neuron-specific gene regulation.
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