Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9

Specific modifications to histones are essential epigenetic markers---heritable changes in gene expression that do not affect the DNA sequence. Methylation of lysine 9 in histone H3 is recognized by heterochromatin protein 1 (HP1), which directs the binding of other proteins to control chromatin structure and gene expression. Here we show that HP1 uses an induced-fit mechanism for recognition of this modification, as revealed by the structure of its chromodomain bound to a histone H3 peptide dimethylated at Nzeta of lysine 9. The binding pocket for the N-methyl groups is provided by three aromatic side chains, Tyr21, Trp42 and Phe45, which reside in two regions that become ordered on binding of the peptide. The side chain of Lys9 is almost fully extended and surrounded by residues that are conserved in many other chromodomains. The QTAR peptide sequence preceding Lys9 makes most of the additional interactions with the chromodomain, with HP1 residues Val23, Leu40, Trp42, Leu58 and Cys60 appearing to be a major determinant of specificity by binding the key buried Ala7. These findings predict which other chromodomains will bind methylated proteins and suggest a motif that they recognize.     

Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

Hedgehog signalling--an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer--may also be an important mediator in human pancreatic carcinoma. Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx-Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.     

Dynamics of Mid-Palaeocene North Atlantic rifting linked with European intra-plate deformations

The process of continental break-up provides a large-scale experiment that can be used to test causal relations between plate tectonics and the dynamics of the Earth's deep mantle. Detailed diagnostic information on the timing and dynamics of such events, which are not resolved by plate kinematic reconstructions, can be obtained from the response of the interior of adjacent continental plates to stress changes generated by plate boundary processes. Here we demonstrate a causal relationship between North Atlantic continental rifting at approximately 62 Myr ago and an abrupt change of the intra-plate deformation style in the adjacent European continent. The rifting involved a left-lateral displacement between the North American-Greenland plate and Eurasia, which initiated the observed pause in the relative convergence of Europe and Africa. The associated stress change in the European continent was significant and explains the sudden termination of a approximately 20-Myr-long contractional intra-plate deformation within Europe, during the late Cretaceous period to the earliest Palaeocene epoch, which was replaced by low-amplitude intra-plate stress-relaxation features. The pre-rupture tectonic stress was large enough to have been responsible for precipitating continental break-up, so there is no need to invoke a thermal mantle plume as a driving mechanism. The model explains the simultaneous timing of several diverse geological events, and shows how the intra-continental stratigraphic record can reveal the timing and dynamics of stress changes, which cannot be resolved by reconstructions based only on plate kinematics.     

A unified mixed-model method for association mapping that accounts for multiple levels of relatedness

As population structure can result in spurious associations, it has constrained the use of association studies in human and plant genetics. Association mapping, however, holds great promise if true signals of functional association can be separated from the vast number of false signals generated by population structure. We have developed a unified mixed-model approach to account for multiple levels of relatedness simultaneously as detected by random genetic markers. We applied this new approach to two samples: a family-based sample of 14 human families, for quantitative gene expression dissection, and a sample of 277 diverse maize inbred lines with complex familial relationships and population structure, for quantitative trait dissection. Our method demonstrates improved control of both type I and type II error rates over other methods. As this new method crosses the boundary between family-based and structured association samples, it provides a powerful complement to currently available methods for association mapping.     

We find them here, we find them there: Functional bacterial amyloid

Protein amyloid is often deposited in connection with neurodegenerative diseases. Such deposits generally possess three principal drawbacks: cytotoxicity, lack of spatial control in their deposition and structural polymorphism. These are typical features of biologically non-optimized systems which have not been exposed to evolutionary pressure. Nevertheless, Nature uses the cross-beta self-organizing principle in many structural contexts where a strong but pliable material is needed. Functional amyloid is found in humans, invertebrates, fungi and, not least, bacteria, in which amyloid may be the rule rather than the exception. Detailed case studies reveal how directed nucleation can use tailor-made proteins optimized to assume a specific amyloid conformation, leading to remarkably robust assemblies. This makes it highly challenging to purify and analyze the products formed in vivo. We contrast pathogenic and in-vitro-formed amyloid with functional amyloid, paying particular reference to bacterial amyloid, and discuss challenges and perspectives in identifying and characterizing this class of protein.     

Macrophage migration inhibitory factor (MIF) modulates trophic signaling through interaction with serine protease HTRA1

Macrophage migration inhibitory factor (MIF), a small conserved protein, is abundant in the immune- and central nervous system (CNS). MIF has several receptors and binding partners that can modulate its action on a cellular level. It is upregulated in neurodegenerative diseases and cancer although its function is far from clear. Here, we report the finding of a new binding partner to MIF, the serine protease HTRA1. This enzyme cleaves several growth factors, extracellular matrix molecules and is implicated in some of the same diseases as MIF. We show that the function of the binding between MIF and HTRA1 is to inhibit the proteolytic activity of HTRA1, modulating the availability of molecules that can change cell growth and differentiation. MIF is therefore the first endogenous inhibitor ever found for HTRA1. It was found that both molecules were present in astrocytes and that the functional binding has the ability to modulate astrocytic activities important in development and disease of the CNS.