Tissue-specific disallowance of housekeeping genes: The other face of cell differentiation

Abstract

We report on a hitherto poorly characterized class of genes that are expressed in all tissues, except in one. Often, these genes have been classified as housekeeping genes, based on their nearly ubiquitous expression. However, the specific repression in one tissue defines a special class of “disallowed genes.” In this paper, we used the intersection-union test to screen for such genes in a multi-tissue panel of genome-wide mRNA expression data. We propose that disallowed genes need to be repressed in the specific target tissue to ensure correct tissue function. We provide mechanistic data of repression with two metabolic examples, exercise-induced inappropriate insulin release and interference with ketogenesis in liver. Developmentally, this repression is established during tissue maturation in the early postnatal period involving epigenetic changes in histone methylation. In addition, tissue-specific expression of microRNAs can further diminish these repressed mRNAs. Together, we provide a systematic analysis of tissue-specific repression of housekeeping genes, a phenomenon that has not been studied so far on a genome-wide basis and, when perturbed, can lead to human disease.

MafA is critical for maintenance of the mature beta cell phenotype in mice

“…3i). These results suggest that beta cell dedifferentiation induced the upregulation of molecules, including in the 'disallowed genes in mature beta cells' [34,35], and reduced the expression of key molecules for beta cells, leading to altered metabolism and impaired insulin release in Mafa KO beta cells.…”

“…3b). Interestingly Slc16a1, which is ubiquitously expressed in most tissues but specifically repressed in adult beta cells (a 'disallowed' gene) [34,35], was upregulated in Mafa KO islets (Fig. 3a).…”

“…Recent systemic genome-wide analyses identified a subset of genes that are repressed specifically in beta cells [34,35]. Inactivation of these genes ensures that beta cells efficiently and adequately secrete insulin in response to glucose stimulation.…”

“…Inactivation of these genes ensures that beta cells efficiently and adequately secrete insulin in response to glucose stimulation. Their repression is differentiation-dependent and established during postnatal maturation, and immature beta cells express these 'disallowed genes' [34,35]. Slc16a1 is one of the most disallowed genes in beta cells, and it was upregulated in dedifferentiated 'empty' beta cells of Mafa KO mice.…”

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat

“…Because beta cells express much lower levels of catalase than most mammalian cells [45,46], they must rely on glutathione oxidation as their primary means of reducing hydrogen peroxide; regeneration of glutathione then requires oxidation of NADPH. Acceleration of glucose metabolism by glucokinase activation is expected to augment NADPH production and thereby enhance beta cell survival by increasing the capacity for hydrogen peroxide detoxification.…”