Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D), but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1D and multiple single-nucleotide polymorphisms in 197 kb of genomic DNA in the IDDM5 interval. We cloned a new gene (SUMO4), encoding small ubiquitin-like modifier 4 protein, in the interval. A substitution (M55V) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with T1D (P = 1.9 x 10(-7)). SUMO4 conjugates to I kappa B alpha and negatively regulates NF kappa B transcriptional activity. The M55V substitution resulted in 5.5 times greater NF kappa B transcriptional activity and approximately 2 times greater expression of IL12B, an NF kappa B-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.

Summary Embryonic development relies on the capacity of progenitor cells to appropriately respond to inductive cues; a cellular property known as developmental competence. Here we report that epigenetic priming of enhancers signifies developmental competence during endodermal lineage diversification. Chromatin mapping during pancreatic and hepatic differentiation of human embryonic stem cells revealed the en masse acquisition of a poised chromatin state at enhancers specific to endoderm-derived cell lineages in gut tube intermediates. Experimentally, the acquisition of this poised enhancer state predicts the ability of endodermal intermediates to respond to inductive signals. Furthermore, these enhancers are first recognized by the pioneer transcription factors FOXA1 and FOXA2 when competence is acquired, while subsequent recruitment of lineage-inductive transcription factors, such as PDX1, leads to enhancer and target gene activation. Together, our results identify the acquisition of a poised chromatin state at enhancers as a mechanism by which progenitor cells acquire developmental competence.

Robust neuroprotective effects have been shown for minocycline. Whether it also protects nonneuronal cells or tissues is unknown. More importantly, the mechanisms of minocylcine protection appear multifaceted and remain to be clarified. Here we show that minocycline can protect kidney epithelial cells in vitro and protect the kidneys from ischemic injury in vivo. We further show that Bcl-2 is a key molecular determinant of minocycline protection. Minocycline protected kidney epithelial cells against apoptosis induced by hypoxia, azide, cisplatin, and staurosporine. The protection occurred at mitochondria, involving the suppression of Bax accumulation, outer membrane damage, and cytochrome c release. Minocycline induced Bcl-2, which accumulated in mitochondria and interacted with death-promoting molecules including Bax, Bak, and Bid. Down-regulation of Bcl-2 by specific antisense oligonucleotides abolished the cytoprotective effects of minocycline. Thus, minocycline can protect neuronal as well as nonneuronal cells and tissues. One mechanism for minocycline protection involves the induction of Bcl-2, an antiapoptotic protein.Minocycline is a semisynthetic derivative of tetracycline, which has been used as an effective antibiotic for decades (1). Recent studies, however, have suggested bioactivities for minocycline that are unrelated to its antimicrobial property. For example, minocycline and related tetracyclines are anti-inflammatory (2). Strikingly, studies within the past a few years have demonstrated a robust neuroprotective effect of minocycline. Minocycline protects neuronal cells and tissues in experimental models of ischemic stroke (3-5), Huntington's disease (6), amyotropic lateral sclerosis (7), traumatic brain injury (8), multiple sclerosis (9), and Parkinson's disease (10, 11). Neuroprotective effects of minocycline can be indirect, through the inhibition of microglial activation and proliferation (3,(11)(12)(13)(14). On the other hand, direct neuronal protection by minocycline has been documented (4, 7, 15-17), probably involving the preservation of mitochondrial integrity and cytochrome c, followed by the suppression of caspase-dependent as well as -independent cell death (7,15). Despite these important findings, two critical questions remain. First, is minocycline protection specific for nervous systems? does minocycline protect nonneuronal cells or tissues? Second and more importantly, what is the molecular basis for minocycline protection? Here we show that minocycline protects kidney epithelial cells against injury and death induced by different types of insults. We further show that minocycline protects kidney from ischemic injury in vivo. A major cellular site for minocycline protection is the mitochondrion. Finally, we have identified Bcl-2 as a key molecular determinant of the cytoprotective effects of minocycline. Bcl-2 is induced by minocycline, accumulates in mitochondria, and may protect the organelles by antagonizing proapoptotic Bax, Bak, and Bid. Down-regulation of Bcl-2 by specific a...

PSS FTEs is also useful in many other types of flexible optoelectronic devices.