Mechanisms of epigenetic inheritance.

The mechanisms by which stable gene expression patterns are inherited during cell division are not well understood. Chromatin is subject to a number of covalent modifications and it is generally believed that the transfer of these modifications between cell generations plays a critical role in inheritance, though how this occurs is a matter of debate. In one proposed model, replication of chromatin in a semi-conservative fashion would allow 'template reading' and 'writing' mechanisms to copy modifications from old histones to new histones. Conversely, if chromatin is replicated in a conservative fashion, then other mechanisms, such as the replacement and/or modification of histones during transcription, may mediate the replication of these modifications. Finally, several recent studies suggest that the faithful replication of DNA methylation patterns may be used to propagate histone modifications associated with gene silencing.

Multiple promoter and enhancer differences likely contribute to augmented G6PC2 expression in human versus mouse pancreatic islet alpha cells.

G6PC2 encodes a glucose-6-phosphatase catalytic subunit that opposes the action of glucokinase in pancreatic islets thereby modulating the sensitivity of insulin and glucagon secretion to glucose. In mice, G6pc2 is expressed at ~20-fold higher levels in ß-cells versus α-cells, whereas in humans G6PC2 is expressed at only ~5-fold higher levels in ß-cells. We therefore hypothesize that G6PC2 likely influences glucagon secretion to a greater degree in humans. With a view to generating a humanized mouse that re-capitulates augmented G6PC2 expression levels in α-cells, we sought to identify the genomic regions that confer differential mouse G6pc2 expression in α-cells versus ß-cells as well as the evolutionary changes that have altered this ratio in humans. Studies in islet-derived cell lines suggest that the elevated G6pc2 expression in mouse ß-cells versus α-cells is mainly due to a difference in the relative activity of the proximal G6pc2 promoter in these cell types. Similarly, the smaller difference in G6PC2 expression between α-cells versus ß-cells in humans is potentially explained by a change in relative proximal G6PC2 promoter activity. However, we show that both glucocorticoid levels and multiple differences in the relative activity of eight transcriptional enhancers between mice and humans likely contribute to differential G6PC2 expression. Finally, we show that a mouse-specific non-coding RNA, Gm13613, whose expression is controlled by G6pc2 enhancer I, does not regulate G6pc2 expression, indicating that altered expression of Gm13613 in a humanized mouse that contains both the human promoter and enhancers, should not affect G6PC2 function.

Stranger than fiction.

Martin introduces a special issue on cephalopods, showcasing their fascinating biology and highlighting recent developments in the field.

Waste not, want not.

When faced with limited resources, organisms evolve ways to conserve. In this editorial, Martin introduces a special issue devoted to economies in biology and highlights key issues, including some interesting examples of conservation and how fixed resource budgets force tradeoffs in life history traits.

Gut check.

Research on the gut microbiome and its relationship to our health, even our behaviors, has captured the public's interest, and the probiotic industry has moved in to capitalize. The field has advanced so quickly that some of the claims may have outpaced the evidence. Cyrus Martin reports.

Wilhelm Hofmeister and the foundations of plant science.

On January 12th 1877, the Grim Reaper visited Wilhelm Hofmeister (Figure 1) for the last time. Having recently witnessed the death of a wife, two daughters, and two sons (only two of his nine children survived him), the German botanist, perhaps succumbing to the weight of his own grief, suffered a series of strokes and then promptly died at the age of 52 in Lindenau, Germany. He has since faded into the dusty annals of 19th century botany, his contributions to our knowledge about plants, how they come into being, develop and interact with their environment, mostly forgotten. In an ode to Hofmeister marking 100 years since his birth, Douglas Haughton Campbell of Stanford University, referring to Hofmeister's studies in comparative morphology, wrote, "…there is no question that Hofmeister's work will remain as probably the most brilliant contribution ever made to this fundamental department of botany" [1]. And in an essay published in Plant Physiology, Donald Kaplan and Todd Cooke went further still, writing, "Frederich Wilhelm Benedikt Hofmeister stands as one of the most remarkable figures in the history of botany and one who made fundamental contributions to all areas of plant biology" [2]. If that wasn't enough, Kaplan and Cooke added "In terms of native genius, he is certainly the peer of both Darwin and Mendel and may have even exceeded them in the breadth and depth of his talents."

The proximal islet-specific glucose-6-phosphatase catalytic subunit-related protein autoantigen promoter is sufficient to initiate but not maintain transgene expression in mouse islets in vivo.

We have previously reported the discovery of an islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) that is predominantly expressed in islet beta-cells. IGRP has recently been identified as a major autoantigen in a mouse model of type 1 diabetes. The analysis of IGRP-chloramphenicol acetyltransferase (CAT) fusion gene expression in transiently transfected islet-derived hamster insulinoma tumor and betaTC-3 cells revealed that the promoter region located between -306 and +3 confers high-level reporter gene expression. To determine whether this same promoter region is sufficient to confer islet beta-cell-specific gene expression in vivo, it was ligated to a beta-galactosidase reporter gene, and transgenic mice expressing the resulting fusion gene were generated. In two independent founder lines, this -306 to +3 promoter region was sufficient to drive beta-galactosidase expression in newborn mouse islets, predominantly in beta-cells, which was initiated during the expected time in development, around embryonic day 12.5. However, unlike the endogenous IGRP gene, beta-galactosidase expression was also detected in the cerebellum. Moreover, beta-galactosidase expression was almost completely absent in adult mouse islets, suggesting that cis-acting elements elsewhere in the IGRP gene are required for determining appropriate IGRP tissue-specific expression and for the maintenance of IGRP gene expression in adult mice.

A re-examination of the pollinator crisis.

Reports of colony collapse disorder in bees and studies showing the toxicity of neonicotinoid pesticides have led to claims that we are experiencing a pollinator crisis. As Cyrus Martin reports, however, the issue is complex with threats to bees being multifold and the status of populations unclear due to a surprising lack of data.

Breathing fresh life into life science education.

In the US, higher education in the life sciences is being overhauled. There is now a move both to change the way we teach biology students, emphasizing more engaging approaches, and to clearly define what it is a student should know. And for advanced degrees, there is a push to prepare students for a range of possible career paths, not just the tenure track. Cyrus Martin reports.

Funding troubles for evolution and ecology.

The human population passed the 7 billion mark last month. As the population grows, the environment, which in turn is necessary for our survival, suffers as a result of increased demand for natural resources and global warming. Key to addressing these challenges will be new knowledge provided by the evolutionary and ecological sciences. But, alarmingly, these areas are underfunded, as Cyrus Martin reports.

Web effects.

Cyrus Martin looks at a study showing how an invasive plant can dramatically alter predator-prey relations.

Foxa2 and MafA regulate islet-specific glucose-6-phosphatase catalytic subunit-related protein gene expression.

Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP/G6PC2) is a major autoantigen in both mouse and human type 1 diabetes. IGRP is selectively expressed in islet beta cells and polymorphisms in the IGRP gene have recently been associated with variations in fasting blood glucose levels and cardiovascular-associated mortality in humans. Chromatin immunoprecipitation (ChIP) assays have shown that the IGRP promoter binds the islet-enriched transcription factors Pax-6 and BETA2. We show here, again using ChIP assays, that the IGRP promoter also binds the islet-enriched transcription factors MafA and Foxa2. Single binding sites for these factors were identified in the proximal IGRP promoter, mutation of which resulted in decreased IGRP fusion gene expression in betaTC-3, Hamster insulinoma tumor (HIT), and Min6 cells. ChiP assays have shown that the islet-enriched transcription factor Pdx-1 also binds the IGRP promoter, but mutational analysis of four Pdx-1 binding sites in the proximal IGRP promoter revealed surprisingly little effect of Pdx-1 binding on IGRP fusion gene expression in betaTC-3 cells. In contrast, in both HIT and Min6 cells mutation of these four Pdx-1 binding sites resulted in a approximately 50% reduction in fusion gene expression. These data suggest that the same group of islet-enriched transcription factors, namely Pdx-1, Pax-6, MafA, BETA2, and Foxa2, directly or indirectly regulate expression of the two major autoantigens in type 1 diabetes.