Modeling a New Water Channel That Allows SET9 to Dimethylate p53

SET9, a protein lysine methyltransferase, has been thought to be capable of transferring only one methyl group to target lysine residues. However, some reports have pointed out that SET9 can dimethylate Lys372 of p53 (p53-K372) and Lys4 of histone H3 (H3-K4). In order to understand how p53 can be dimethylated by SET9, we measured the radius of the channel that surrounds p53-K372, first on the basis of the crystal structure of SET9, and we show that the channel is not suitable for water movement. Second, molecular dynamic (MD) simulations were carried out for 204 ns on the crystal structure of SET9. The results show that water leaves the active site of SET9 through a new channel, which is made of G292, A295, Y305 and Y335. In addition, the results of molecular docking and MD simulations indicate that the new water channel continues to remain open when S-adenosyl-L-methionine (AdoMet) or S-adenosyl-L-homocysteine (AdoHcy) is bound to SET9. The changes in the radii of these two channels were measured in the equilibrium phase at the constant temperature of 300 K. The results indicate that the first channel still does not allow water to get into or out of the active site, but the new channel is large enough to allow this water to circulate. Our results indicate that water can be removed from the active site, an essential process for allowing the dimethylation reaction to occur

Interaction of SET domains with histones and nucleic acid structures in active chromatin

Changes in the normal program of gene expression are the basis for a number of human diseases. Epigenetic control of gene expression is programmed by chromatin modifications—the inheritable “histone code”—the major component of which is histone methylation. This chromatin methylation code of gene activity is created upon cell differentiation and is further controlled by the “SET” (methyltransferase) domain proteins which maintain this histone methylation pattern and preserve it through rounds of cell division. The molecular principles of epigenetic gene maintenance are essential for proper treatment and prevention of disorders and their complications. However, the principles of epigenetic gene programming are not resolved. Here we discuss some evidence of how the SET proteins determine the required states of target genes and maintain the required levels of their activity. We suggest that, along with other recognition pathways, SET domains can directly recognize the nucleosome and nucleic acids intermediates that are specific for active chromatin regions

The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis

The orphan nuclear receptor NR5A2 is necessary for the stem-like properties of the epiblast of the pre-gastrulation embryo and for cellular and physiological homeostasis of endoderm-derived organs postnatally. Using conditional gene inactivation, we show that Nr5a2 also plays crucial regulatory roles during organogenesis. During the formation of the pancreas, Nr5a2 is necessary for the expansion of the nascent pancreatic epithelium, for the subsequent formation of the multipotent progenitor cell (MPC) population that gives rise to pre-acinar cells and bipotent cells with ductal and islet endocrine potential, and for the formation and differentiation of acinar cells. At birth, the NR5A2-deficient pancreas has defects in all three epithelial tissues: a partial loss of endocrine cells, a disrupted ductal tree and a >90% deficit of acini. The acinar defects are due to a combination of fewer MPCs, deficient allocation of those MPCs to pre-acinar fate, disruption of acinar morphogenesis and incomplete acinar cell differentiation. NR5A2 controls these developmental processes directly as well as through regulatory interactions with other pancreatic transcriptional regulators, including PTF1A, MYC, GATA4, FOXA2, RBPJL and MIST1 (BHLHA15). In particular, Nr5a2 and Ptf1a establish mutually reinforcing regulatory interactions and collaborate to control developmentally regulated pancreatic genes by binding to shared transcriptional regulatory regions. At the final stage of acinar cell development, the absence of NR5A2 affects the expression of Ptf1a and its acinar specific partner Rbpjl, so that the few acinar cells that form do not complete differentiation. Nr5a2 controls several temporally distinct stages of pancreatic development that involve regulatory mechanisms relevant to pancreatic oncogenesis and the maintenance of the exocrine phenotype. 2014. Published by The Company of Biologists Lt

The Cinderella Complex: punishment, society and community sanctions

This article explores the neglect of community sanctions (probation, parole etc.) in contemporary punishment and society scholarship, and seeks to understand why this part of the penal field has not attracted significant attention from researchers, despite expansion and diversification in a variety of jurisdictions. Following a review of punishment and society scholarship, which confirms the ‘Cinderella’ status of community sanctions, three arguments are proposed to help make sense of this finding. These concern the problems of language and labelling, the (in)visibility of the field and the debateable penal character of community sanctions. The article concludes with a ‘call to arms’ for punishment and society scholars, which entails recognising Cinderella as a key actor in the stories we tell about penal change, and pushing her out of the shadows of punishment and society scholarship

Chemical differentiation, cold storage and remobilization of magma in the Earth's crust

The formation, storage and chemical differentiation of magma in the Earth’s crust is of fundamental importance in igneous geology and volcanology. Recent data are challenging the high-melt-fraction ‘magma chamber’ paradigm that has underpinned models of crustal magmatism for over a century, suggesting instead that magma is normally stored in low-melt-fraction ‘mush reservoirs’1,2,3,4,5,6,7,8,9. A mush reservoir comprises a porous and permeable framework of closely packed crystals with melt present in the pore space1,10. However, many common features of crustal magmatism have not yet been explained by either the ‘chamber’ or ‘mush reservoir’ concepts1,11. Here we show that reactive melt flow is a critical, but hitherto neglected, process in crustal mush reservoirs, caused by buoyant melt percolating upwards through, and reacting with, the crystals10. Reactive melt flow in mush reservoirs produces the low-crystallinity, chemically differentiated (silicic) magmas that ascend to form shallower intrusions or erupt to the surface11,12,13. These magmas can host much older crystals, stored at low and even sub-solidus temperatures, consistent with crystal chemistry data6,7,8,9. Changes in local bulk composition caused by reactive melt flow, rather than large increases in temperature, produce the rapid increase in melt fraction that remobilizes these cool- or cold-stored crystals. Reactive flow can also produce bimodality in magma compositions sourced from mid- to lower-crustal reservoirs14,15. Trace-element profiles generated by reactive flow are similar to those observed in a well studied reservoir now exposed at the surface16. We propose that magma storage and differentiation primarily occurs by reactive melt flow in long-lived mush reservoirs, rather than by the commonly invoked process of fractional crystallization in magma chambers[14]