21,129 research outputs found
Recent evidence that TADs and chromatin loops are dynamic structures.
Mammalian genomes are folded into spatial domains, which regulate gene expression by modulating enhancer-promoter contacts. Here, we review recent studies on the structure and function of Topologically Associating Domains (TADs) and chromatin loops. We discuss how loop extrusion models can explain TAD formation and evidence that TADs are formed by the ring-shaped protein complex, cohesin, and that TAD boundaries are established by the DNA-binding protein, CTCF. We discuss our recent genomic, biochemical and single-molecule imaging studies on CTCF and cohesin, which suggest that TADs and chromatin loops are dynamic structures. We highlight complementary polymer simulation studies and Hi-C studies employing acute depletion of CTCF and cohesin, which also support such a dynamic model. We discuss the limitations of each approach and conclude that in aggregate the available evidence argues against stable loops and supports a model where TADs are dynamic structures that continually form and break throughout the cell cycle
A computational model for histone mark propagation reproduces the distribution of heterochromatin in different human cell types
Chromatin is a highly compact and dynamic nuclear structure that consists of
DNA and associated proteins. The main organizational unit is the nucleosome,
which consists of a histone octamer with DNA wrapped around it. Histone
proteins are implicated in the regulation of eukaryote genes and they carry
numerous reversible post-translational modifications that control DNA-protein
interactions and the recruitment of chromatin binding proteins.
Heterochromatin, the transcriptionally inactive part of the genome, is densely
packed and contains histone H3 that is methylated at Lys 9 (H3K9me). The
propagation of H3K9me in nucleosomes along the DNA in chromatin is antagonizing
by methylation of H3 Lysine 4 (H3K4me) and acetylations of several lysines,
which is related to euchromatin and active genes. We show that the related
histone modifications form antagonized domains on a coarse scale. These histone
marks are assumed to be initiated within distinct nucleation sites in the DNA
and to propagate bi-directionally. We propose a simple computer model that
simulates the distribution of heterochromatin in human chromosomes. The
simulations are in agreement with previously reported experimental observations
from two different human cell lines. We reproduced different types of barriers
between heterochromatin and euchromatin providing a unified model for their
function. The effect of changes in the nucleation site distribution and of
propagation rates were studied. The former occurs mainly with the aim of
(de-)activation of single genes or gene groups and the latter has the power of
controlling the transcriptional programs of entire chromosomes. Generally, the
regulatory program of gene transcription is controlled by the distribution of
nucleation sites along the DNA string.Comment: 24 pages,9 figures, 1 table + supplementary materia
Thermodynamic pathways to genome spatial organization in the cell nucleus
The architecture of the eukaryotic genome is characterized by a high degree of spatial organization. Chromosomes occupy preferred territories correlated to their state of activity and, yet, displace their genes to interact with remote sites in complex patterns requiring the orchestration of a huge number of DNA loci and molecular regulators. Far from random, this organization serves crucial functional purposes, but its governing principles remain elusive. By computer simulations of a Statistical Mechanics model, we show how architectural patterns spontaneously arise from the physical interaction between soluble binding molecules and chromosomes via collective thermodynamics mechanisms. Chromosomes colocalize, loops and territories form and find their relative positions as stable hermodynamic states. These are selected by “thermodynamic switches” which are regulated by concentrations/affinity of soluble mediators and by number/location of their attachment sites along chromosomes. Our “thermodynamic switch model” of nuclear architecture, thus, explains on quantitative grounds how well known cell strategies of upregulation of DNA binding proteins or modification of chromatin structure can dynamically shape the organization of the nucleus
Systems analysis of host-parasite interactions.
Parasitic diseases caused by protozoan pathogens lead to hundreds of thousands of deaths per year in addition to substantial suffering and socioeconomic decline for millions of people worldwide. The lack of effective vaccines coupled with the widespread emergence of drug-resistant parasites necessitates that the research community take an active role in understanding host-parasite infection biology in order to develop improved therapeutics. Recent advances in next-generation sequencing and the rapid development of publicly accessible genomic databases for many human pathogens have facilitated the application of systems biology to the study of host-parasite interactions. Over the past decade, these technologies have led to the discovery of many important biological processes governing parasitic disease. The integration and interpretation of high-throughput -omic data will undoubtedly generate extraordinary insight into host-parasite interaction networks essential to navigate the intricacies of these complex systems. As systems analysis continues to build the foundation for our understanding of host-parasite biology, this will provide the framework necessary to drive drug discovery research forward and accelerate the development of new antiparasitic therapies
Dissecting the dynamics of signaling events in the BMP, WNT, and NODAL cascade during self-organized fate patterning in human gastruloids.
During gastrulation, the pluripotent epiblast self-organizes into the 3 germ layers-endoderm, mesoderm and ectoderm, which eventually form the entire embryo. Decades of research in the mouse embryo have revealed that a signaling cascade involving the Bone Morphogenic Protein (BMP), WNT, and NODAL pathways is necessary for gastrulation. In vivo, WNT and NODAL ligands are expressed near the site of gastrulation in the posterior of the embryo, and knockout of these ligands leads to a failure to gastrulate. These data have led to the prevailing view that a signaling gradient in WNT and NODAL underlies patterning during gastrulation; however, the activities of these pathways in space and time have never been directly observed. In this study, we quantify BMP, WNT, and NODAL signaling dynamics in an in vitro model of human gastrulation. Our data suggest that BMP signaling initiates waves of WNT and NODAL signaling activity that move toward the colony center at a constant rate. Using a simple mathematical model, we show that this wave-like behavior is inconsistent with a reaction-diffusion-based Turing system, indicating that there is no stable signaling gradient of WNT/NODAL. Instead, the final signaling state is homogeneous, and spatial differences arise only from boundary effects. We further show that the durations of WNT and NODAL signaling control mesoderm differentiation, while the duration of BMP signaling controls differentiation of CDX2-positive extra-embryonic cells. The identity of these extra-embryonic cells has been controversial, and we use RNA sequencing (RNA-seq) to obtain their transcriptomes and show that they closely resemble human trophoblast cells in vivo. The domain of BMP signaling is identical to the domain of differentiation of these trophoblast-like cells; however, neither WNT nor NODAL forms a spatial pattern that maps directly to the mesodermal region, suggesting that mesoderm differentiation is controlled dynamically by the combinatorial effect of multiple signals. We synthesize our data into a mathematical model that accurately recapitulates signaling dynamics and predicts cell fate patterning upon chemical and physical perturbations. Taken together, our study shows that the dynamics of signaling events in the BMP, WNT, and NODAL cascade in the absence of a stable signaling gradient control fate patterning of human gastruloids.R01 GM126122 - NIGMS NIH HHSPublished versio
Complex networks theory for analyzing metabolic networks
One of the main tasks of post-genomic informatics is to systematically
investigate all molecules and their interactions within a living cell so as to
understand how these molecules and the interactions between them relate to the
function of the organism, while networks are appropriate abstract description
of all kinds of interactions. In the past few years, great achievement has been
made in developing theory of complex networks for revealing the organizing
principles that govern the formation and evolution of various complex
biological, technological and social networks. This paper reviews the
accomplishments in constructing genome-based metabolic networks and describes
how the theory of complex networks is applied to analyze metabolic networks.Comment: 13 pages, 2 figure
Theoretical analysis of the role of chromatin interactions in long-range action of enhancers and insulators
Long-distance regulatory interactions between enhancers and their target
genes are commonplace in higher eukaryotes. Interposed boundaries or insulators
are able to block these long distance regulatory interactions. The mechanistic
basis for insulator activity and how it relates to enhancer
action-at-a-distance remains unclear. Here we explore the idea that topological
loops could simultaneously account for regulatory interactions of distal
enhancers and the insulating activity of boundary elements. We show that while
loop formation is not in itself sufficient to explain action at a distance,
incorporating transient non-specific and moderate attractive interactions
between the chromatin fibers strongly enhances long-distance regulatory
interactions and is sufficient to generate a euchromatin-like state. Under
these same conditions, the subdivision of the loop into two topologically
independent loops by insulators inhibits inter-domain interactions. The
underlying cause of this effect is a suppression of crossings in the contact
map at intermediate distances. Thus our model simultaneously accounts for
regulatory interactions at a distance and the insulator activity of boundary
elements. This unified model of the regulatory roles of chromatin loops makes
several testable predictions that could be confronted with \emph{in vitro}
experiments, as well as genomic chromatin conformation capture and fluorescent
microscopic approaches.Comment: 10 pages, originally submitted to an (undisclosed) journal in May
201
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