25 research outputs found
Stratification of telomerase activity in cancer reveals associations with senescence and genomic instability
No full textTelomerase activity plays an essential role in tumor growth and varies across cancers, typically classified as low or high based on its expression level. This variation is pertinent to cancer-related mechanisms and hallmarks of cellular aging. However, the relationship between distinct telomerase activity groups (low or high) and specific molecular programs across tumor types remains poorly defined, largely due to the absence of a robust classification framework. Here, we applied EXTEND, our previously validated computational model for quantifying telomerase activity, to stratify tumors into low and high telomerase activity groups across diverse cancer types using an unsupervised, data-driven approach. We analyzed over 10,000 tumor samples from bulk RNA sequencing data in The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), as well as more than 10,000 single cells from single-cell and spatial transcriptomic datasets. Our analyses revealed that high telomerase activity group was strongly associated with genomic instability across majority of cancers, whereas low telomerase activity group was enriched for cellular senescence, inflammation, reactive oxygen species (ROS), and MAPK signaling pathways. Notably, cellular senescence, a hallmark of aging, was predominant in older individuals across cancers, normal tissues, and developmental stages. Together, our findings establish a comprehensive framework linking telomerase activity groups to distinct molecular and cellular phenotypes across human cancers and reveal that low telomerase activity corresponds to a senescence-like transcriptional program that is generally associated with favorable survival outcomes. Conclusively, our work provides a unifying framework for understanding telomerase-associated heterogeneity across a broad compendium of tumors
Comparative modeling studies of rat amiloride-sensitive cation channel 1, neuronal isoform b
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Decoding Common Features of Neurodegenerative Disorders: From Differentially Expressed Genes to Pathways
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HCVS: Pinpointing Chromatin States Through Hierarchical Clustering and Visualization Scheme
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Background:
Specific combinations of Histone Modifications (HMs) contributing towards
histone code hypothesis lead to various biological functions. HMs combinations have been utilized by
various studies to divide the genome into different regions. These study regions have been classified as
chromatin states. Mostly Hidden Markov Model (HMM) based techniques have been utilized for this
purpose. In case of chromatin studies, data from Next Generation Sequencing (NGS) platforms is being
used. Chromatin states based on histone modification combinatorics are annotated by mapping them to
functional regions of the genome. The number of states being predicted so far by the HMM tools have
been justified biologically till now.
Objective:
The present study aimed at providing a computational scheme to identify the underlying
hidden states in the data under consideration.
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Methods: We proposed a computational scheme HCVS based on hierarchical clustering and
visualization strategy in order to achieve the objective of study.
Results:
We tested our proposed scheme on a real data set of nine cell types comprising of nine
chromatin marks. The approach successfully identified the state numbers for various possibilities. The
results have been compared with one of the existing models as well which showed quite good
correlation.
Conclusion:
The HCVS model not only helps in deciding the optimal state numbers for a particular data
but it also justifies the results biologically thereby correlating the computational and biological aspects.</jats:sec
Molecular mechanism of reversed temperature dependence of ATP synthesis in glacier ice worms
No full textThe F0F1 ATP synthase enzyme is highly conserved across species. The F0F1 is a reversible motor, where the counterclockwise rotation of the rotor portion of F0 (known as the c-ring and present in the membrane-embedded F0 domain) produces ATP, and the clockwise rotation induces ATP hydrolysis. In a surprising contrast to temperate organisms, glacier ice worms display elevated ATP levels as temperatures decline. The increased energy expenditure is used as a strategy for survival at cold temperatures, but the mechanism is unknown. More specifically, an ice worm-specific, 18 amino acid extension with regularly spaced histidine residues was previously found to be fused to the carboxy-terminal of the ATP6 subunit generating a proton shuttling domain projecting away from the F0 exit pore. The role of this C-terminal extension in the temperature dependence ATP synthesis in ice worms is undetermined. To investigate the underlying mechanism of elevated ATP levels in glacier ice worms, we sought to understand the effects of temperature on the dynamics of the F0F1 ATP synthase of ice worm, yeast and ice worm without the ATP6 extension. We conducted all-atomistic MD simulations of the F0 domain subunits at different temperatures to evaluate the effect of sequence on temperature dependence. We also measured the rotational diffusion of the cring as a function of temperature to evaluate the change in the rotation angles of the c-ring around the z-axis in clock-and counter-clockwise directions. Our results suggest that the rotational diffusion of the c-ring is temperature-dependent, and the ATP6 extension exacerbates the difference in rotational diffusion at varying temperatures.M.S.Includes bibliographical reference
