Promiscuous Gene Expression Research Articles

Contrasting models of promiscuous gene expression by thymic epithelium

Medullary thymic epithelial cells (mTECs) express a broad spectrum of tissue- restricted self-antigens (TRAs), which are required for the development of central tolerance. A new study suggests that TRA expression is a specialized property of terminally differentiated mTECs. However, as discussed here, an alternative model—whereby TRA expression is regulated by conserved developmental programs active in developing mTECs—may be equally plausible.

Neuronal expression of the transcription factor Gli1 using the Talpha1 alpha-tubulin promoter is neuroprotective in an experimental model of Parkinson's disease.

Nigrostriatal neurons degenerate during Parkinson's disease. Experimentally, neurotoxins such as 6-hydroxydopamine (6-OHDA) in rodents, and MPTP in mice and non-human primates, are used to model the disease-induced degeneration of midbrain dopaminergic neurons. Glial-cell-derived neurotrophic factor (GDNF) is a very powerful neuroprotector of dopaminergic neurons in all species examined. However, recent reports have indicated the possibility that GDNF may, in the long term and if expressed in an unregulated manner, exert untoward effects on midbrain dopaminergic neuronal structure and function. Although GDNF remains a powerful neurotrophin, the search for alternative therapies based on alternative and complementary mechanisms of action to GDNF is warranted. Recently, recombinant adenovirus-derived vectors encoding the differentiation factor Sonic Hedgehog (Shh) and its downstream transcriptional activator (Gli1) were shown to protect dopaminergic neurons in the substantia nigra pars compacta from 6-OHDA-induced neurotoxicity in rats in vivo. A pancellular human CMV (hCMV) promoter was used to drive the expression of both Shh and Gli1. Since Gli1 is a transcription factor and therefore exerts its actions intracellularly, we decided to test whether expression of Gli1 within neurons would be effective for neuroprotection. We demonstrate that neuronal-specific expression of Gli1 using the neuron-specific Talpha1 alpha-tubulin (Talpha1) promoter was neuroprotective, and its efficiency was comparable to the pancellular strong viral hCMV promoter. These results suggest that expression of the transcription factor Gli1 solely within neurons is neuroprotective for dopaminergic neurons in vivo and, furthermore, that neuronal-specific promoters are effective within the context of adenovirus-mediated gene therapy-induced neuroprotection of dopaminergic midbrain neurons. Since cell-type specific promoters are known to be weaker than the viral hCMV promoter, our data demonstrate that neuronal-specific expression of transcription factors is an effective, specific, and sufficient targeted approach for neurological gene therapy applications, potentially minimizing side effects due to unrestricted promiscuous gene expression within target tissues.

The nature of stem cells: state rather than entity

Stem cells are endowed with self-renewal and multipotential differentiation capacities. Contrary to the expectation that stem cells would selectively express specific genes, these cells have a highly promiscuous gene-expression pattern. Here, I suggest that the transient stem cell state, termed the 'stem state', may be assumed by any cell and that the search for specific genes expressed by all stem cells, which would characterize the stem cell as a cell type, might be futile.

Mesenchymal stem cells: harnessing cell plasticity to tissue and organ repair

Plastic behavior of cells is a hallmark of embryonic development. The emergence of primary mesenchyme from within the inner cell mass entails the first epithelial–mesenchymal transition step that is then followed by sequential transitions; the formation of new tissues and organs requires transitions from mesenchyme into epithelium and vice versa. Although it is currently believed that in the adult such transitions do not persist, the frequent occurrence of mesenchymal stem cells (MSCs) in various tissues of the adult organisms, and the reported plasticity of such adult mesenchymal cells, raises the question as to whether the frequency of mesenchymal epithelial transitions in the adult have been underestimated. Indeed, adult mesenchymal stem cells have been reported to differentiate in culture into a multitude of mature cell types including epithelial cells. This opens the way to the use of these stem cells for the construction of new tissues and organs for therapeutic purposes, but the question is still open as to whether mesenchymal stem cells transdifferentiate also in vivo. The molecular mechanism that underlies the plasticity of mesenchymal stem cells and their capacity to transdifferentiate is unresolved. We found that these cells have a promiscuous gene expression pattern; mesenchymal cells, whether primary or cloned cell lines, express T cell receptor (TCR) β and α genes, along with other components of the TCR complex. These cells may therefore be in a standby state, in which many gene families are expressed at a low level thereby making the cell readily capable of shifting fates.

Organization of thymic medullary epithelial heterogeneity: implications for mechanisms of epithelial differentiation.

There are accumulating data to show that thymic epithelium expresses a remarkable array of molecules previously considered to be tissue-specific antigens, such as parathyroid hormone, thyroglobulin, insulin, and C-reactive protein. From an immunological perspective, this property of thymic epithelium would provide an ideal mechanism to effect central tolerance of epithelial-restricted antigens. However, from a mechanistic perspective, this phenomenon remains mysterious. Two explanations have been proposed. One invokes promiscuous gene expression by medullary thymic epithelial cells that would allow transient derepression of selected gene expression. The other proposes that the expression of tissue-restricted genes by thymic epithelium reflects alternate pathways of epithelial development by small numbers of cells to form a mosaic of different epithelial types within the thymus. Here we show thymic expression of lung-associated gene products by an organized epithelial 'organoid' with ultrastructural features of respiratory epithelium and present data suggesting that the thymus also contains structures that ultrastructurally and phenotypically resemble solitary thyroid follicles. Based on these data, it is proposed that some thymic epithelial progenitor cells resemble pharyngeal endoderm in terms of their developmental potential and that alternative differentiation fates taken by these cells serve to maintain the spectrum of epithelial 'self' in the thymus.

Myeloid or Lymphoid Promiscuity as a Critical Step in Hematopoietic Lineage Commitment

We demonstrate here that “promiscuous” expression of myeloid or lymphoid genes precedes lineage commitment in hematopoiesis. Prospectively purified single common myeloid progenitors (CMPs) coexpress myelo-erythroid but not lymphoid genes, whereas single common lymphoid progenitors (CLPs) coexpress T and B lymphoid but not myeloid genes. Genes unrelated to the adopted lineage are downregulated in bipotent and monopotent descendants of CMPs and CLPs. Promiscuous gene expression does not alter the biological potential of multipotent progenitors: CMPs with an activated endogenous M lysozyme locus yield normal proportions of myelo-erythroid colonies, and CLPs expressing the pre-T cell receptor α gene differentiate into normal numbers of B cells. Thus, the accessibility for multiple myeloid or lymphoid programs promiscuously may allow flexibility in fate commitments at these multipotent stages.