155 research outputs found
Analysis of Genetic Interaction Maps Reveals Functional Pleiotropy
Epistatic or genetic interactions, representing the effects of mutations on the phenotypes caused by other mutations, can be very helpful for uncovering functional relationships between genes. Recently, the Epistasis Miniarray Profile (E-MAP) method has emerged as a powerful approach for identifying such interactions systematically. As part of this approach, hierarchical clustering is used to partition genes into groups on the basis of the similarity between their global interaction profiles. Here we present an original biclustering algorithm for identifying groups of functionally related genes from E-MAP data in a manner that allows individual genes to be assigned to more than one functional group. This enables investigation of the pleiotropic nature of gene function, a goal that cannot be achieved with hierarchical clustering. The performance of our algorithm is illustrated by applying it to two E-MAP datasets and an E-MAP-like in silico dataset for the yeast S. cerevisiae. In addition to identifying the majority of the functional modules reported in these studies, our algorithm uncovers many recently documented and novel multi-functional relationships between genes and gene groups
RhoA-ROCK signaling is involved in contraction-mediated inhibition of SERCA2a expression in cardiomyocytes
In neonatal ventricular cardiomyocytes (NVCM), decreased contractile activity stimulates sarco-endoplasmic reticulum Ca2+-ATPase2a (SERCA2a), analogous to reduced myocardial load in vivo. This study investigated in contracting NVCM the role of load-dependent RhoA-ROCK signaling in SERCA2a regulation. Contractile arrest of NVCM resulted in low peri-nuclear localized RhoA levels relative to contracting NVCM. In arrested NVCM, ROCK activity was decreased (59%) and paralleled a loss in F-actin levels. Y-27632-induced ROCK inhibition in contracting NVCM increased SERCA2a messenger RNA expression by 150%. This stimulation was transcriptional, as evident from transfections with the SERCA2a promoter. A reciprocal effect of Y-27632 treatment on the promoter activity of atrial natriuretic factor was observed. SERCA2a transcription was not altered by co-transfection of the RhoA-ROCK-dependent serum response factor (SRF) alone or in combination with myocardin. Furthermore, GATA4, another ROCK-dependent transcription factor, induced rather than repressed SERCA2a transcription. This study shows that contractile activity suppresses SERCA2a gene expression via RhoA-ROCK-dependent transcription modulation. This modulation is likely to be accomplished by a transcription factor other than SRF, myocardin, or GATA4
Expanding the Landscape of Chromatin Modification (CM)-Related Functional Domains and Genes in Human
Chromatin modification (CM) plays a key role in regulating transcription, DNA replication, repair and recombination. However, our knowledge of these processes in humans remains very limited. Here we use computational approaches to study proteins and functional domains involved in CM in humans. We analyze the abundance and the pair-wise domain-domain co-occurrences of 25 well-documented CM domains in 5 model organisms: yeast, worm, fly, mouse and human. Results show that domains involved in histone methylation, DNA methylation, and histone variants are remarkably expanded in metazoan, reflecting the increased demand for cell type-specific gene regulation. We find that CM domains tend to co-occur with a limited number of partner domains and are hence not promiscuous. This property is exploited to identify 47 potentially novel CM domains, including 24 DNA-binding domains, whose role in CM has received little attention so far. Lastly, we use a consensus Machine Learning approach to predict 379 novel CM genes (coding for 329 proteins) in humans based on domain compositions. Several of these predictions are supported by very recent experimental studies and others are slated for experimental verification. Identification of novel CM genes and domains in humans will aid our understanding of fundamental epigenetic processes that are important for stem cell differentiation and cancer biology. Information on all the candidate CM domains and genes reported here is publicly available
Searching for network modules
When analyzing complex networks a key target is to uncover their modular
structure, which means searching for a family of modules, namely node subsets
spanning each a subnetwork more densely connected than the average. This work
proposes a novel type of objective function for graph clustering, in the form
of a multilinear polynomial whose coefficients are determined by network
topology. It may be thought of as a potential function, to be maximized, taking
its values on fuzzy clusterings or families of fuzzy subsets of nodes over
which every node distributes a unit membership. When suitably parametrized,
this potential is shown to attain its maximum when every node concentrates its
all unit membership on some module. The output thus is a partition, while the
original discrete optimization problem is turned into a continuous version
allowing to conceive alternative search strategies. The instance of the problem
being a pseudo-Boolean function assigning real-valued cluster scores to node
subsets, modularity maximization is employed to exemplify a so-called quadratic
form, in that the scores of singletons and pairs also fully determine the
scores of larger clusters, while the resulting multilinear polynomial potential
function has degree 2. After considering further quadratic instances, different
from modularity and obtained by interpreting network topology in alternative
manners, a greedy local-search strategy for the continuous framework is
analytically compared with an existing greedy agglomerative procedure for the
discrete case. Overlapping is finally discussed in terms of multiple runs, i.e.
several local searches with different initializations.Comment: 10 page
OrthoNets: simultaneous visual analysis of orthologs and their interaction neighborhoods across different organisms
Motivation: Protein interaction networks contain a wealth of biological information, but their large size often hinders cross-organism comparisons. We present OrthoNets, a Cytoscape plugin that displays proteinβprotein interaction (PPI) networks from two organisms simultaneously, highlighting orthology relationships and aggregating several types of biomedical annotations. OrthoNets also allows PPI networks derived from experiments to be overlaid on networks extracted from public databases, supporting the identification and verification of new interactors. Any newly identified PPIs can be validated by checking whether their orthologs interact in another organism
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