Biology subjects

Panchenko, A. R.

Publications and source records attributed to Panchenko, A. R..

5 recordsLinked to original sources

bioRxiv2025

Molecular Dynamics-Guided All-Atom Reconstruction of Cryo-ET Maps Reveals Mechanisms of Histone Tail-Mediated Chromatin Compaction

Dynamics and physical state of chromatin are crucial in regulating gene expression, DNA replication, and repair. Intrinsically disordered histone tails were previously recognized as key modulators of chromatin states. However, detailed atomistic mechanisms by which histone tail dynamics are associated with chromatin compaction and higher-order chromatin organization remain poorly understood. In this work, we combine extensive all-atom molecular dynamics simulations of tri-nucleosomes with cryo-electron tomography (Cryo-ET) of native nucleosome arrays to investigate histone tail-mediated chromatin folding. Our approach offers distinct advantages as it elucidates realistic inter- and intra-nucleosomal interactions and DNA conformations derived from physics-based MD simulations, enabling a more accurate and physically grounded interpretation of Cryo-ET data. The results reveal that histone tails promote chromatin compaction and constrain tri-nucleosome unfolding via three major patterns: through histone-DNA interactions, histone H2A-H4 and H3-H4 tail-tail interactions. Notably, the distributions of MD-generated structural parameters of tri-nucleosomes with truncated histone tails were found to be in strong agreement with those of experimental open chromatin arrays with widely spaced nucleosomes, whereas the system with histone tails resembled more condensed chromatin. These findings provide mechanistic insights into how histone tails may mediate chromatin folding at the atomistic scale and underscore the dual role of histone tails in both structural compaction and inter-nucleosomal communication.

biophysics↗

bioRxiv2024

Cancer Histone Mutations Impact Binding and DNA Repair Processes, Leading to Increased Mutagenesis

Histones are key epigenetic factors for regulating the accessibility and compaction of eukaryotic genomes, affecting the replication, repair, and expression of DNA. Recent studies have demonstrated that histone missense mutations can perturb normal histone function, promoting the development of phenotypically distinguishable cancers. However, most histone mutations observed in cancer patients remain enigmatic in their potential to promote cancer development. To assess the oncogenic potential of histone missense mutations, we have gathered whole-exome sequencing data for the tumors of over 12,000 patients. Overall, histone mutations occurred in about 16% of cancer patients, although specific cancer types showed substantially higher rates. Using a combination of genomic, structural, and biophysical analyses, we found several predominant modes of action, where cancer missense mutations in histones affected acidic patches and protein binding interfaces in a cancer-specific manner and targeted interaction sites with specific DNA repair proteins. Consistent with this finding, we observed a high tumour mutational burden in patients with histone mutations affecting interactions of DNA repair proteins. We also identified potential cancer driver mutations in several histone genes, including histone H4-a highly conserved histone without previously documented driver mutations.

bioinformatics↗

bioRxiv2020

Binding of regulatory proteins to nucleosomes is modulated by dynamic histone tails

Despite histone tails critical roles in epigenetic regulation, little is known about mechanisms of how histone tails modulate the nucleosomal DNA solvent accessibility and recognition of nucleosomes by other macromolecules. Here we generate extensive atomic level conformational ensembles of histone tails in the context of the full human nucleosome, totaling 26 microseconds of molecular dynamics simulations. We explore the histone tail binding with the nucleosomal and linker DNA and observe rapid conformational transitions between bound and unbound states allowing us to estimate kinetic and thermodynamic properties of the histone tail-DNA interactions. Different histone types exhibit distinct, although conformationally heterogeneous, binding modes and each histone type occludes specific DNA regions from the solvent. Using a comprehensive set of experimental data on nucleosome structural complexes, we find that majority of the studied nucleosome-binding proteins and histone tails target mutually exclusive regions on nucleosomal or linker DNA around the super-helical locations {+/-}1, {+/-}2, and {+/-}7. This finding is explained within the generalized competitive binding and tail displacement models of partners recruitment to nucleosomes. Finally, we demonstrate the crosstalk between different histone post-translational modifications, where charge-altering modifications and mutations typically suppress tail-DNA interactions and enhance histone tail dynamics.

biophysics↗

bioRxiv2018

Nucleotide and codon background mutability shape cancer mutational spectrum and advance driver mutation identification

Identifying driver mutations in cancer is notoriously difficult. To date, recurrence of a mutation in patients remains one of the most reliable markers of mutation driver status. However, some mutations are more likely to occur than others due to differences in background mutation rates arising from various forms of infidelity of DNA replication and repair machinery, endogenous, and exogenous mutagens.\n\nWe used cancer-type and mutagen-specific mutability to study the contribution of background processes of mutagenesis and DNA repair in shaping the observed mutational spectrum in cancer. We developed and tested probabilistic model that adjusts the number of mutation recurrences in patients by background mutability in order to find mutations which may be under selection in cancer.\n\nWe showed that observed recurrence frequency of cancer mutations scaled with the background mutability, especially for tumor suppressor genes. In oncogenes, however, highly recurring mutations were characterized by relatively low mutability, resulting in a U-shaped trend. Mutations not yet observed in any tumor had relatively low mutability values, indicating that background mutability might limit the mutation occurrence.\n\nWe compiled a dataset of missense mutations from 58 genes with experimentally validated functional and transforming impacts from different studies. We found that mutability of driver mutations was lower than the mutability of passengers and consequently adjusting mutation recurrence frequency by mutability significantly improved ranking of mutations and driver prediction. Even though no training on existing data was involved, our approach performed similar or better to the existing state-of-the-art methods.\n\nAvailabilityhttps://www.ncbi.nlm.nih.gov/research/mutagene/gene

cancer biology↗

bioRxiv2018

Integrated proteogenomic analysis of metastatic thoracic tumors identifies APOBEC mutagenesis and copy number alterations as drivers of proteogenomic tumor evolution and heterogeneity

Elucidation of the proteogenomic evolution of metastatic tumors may offer insight into the poor prognosis of patients harboring metastatic disease. We performed whole-exome and transcriptome sequencing, copy number alterations (CNA) and mass spectrometry-based quantitative proteomics of 37 lung adenocarcinoma (LUAD) and thymic carcinoma (TC) metastases obtained by rapid autopsy and found evidence of patient-specific, multi-dimensional heterogeneity. Extreme mutational heterogeneity was evident in a subset of patients whose tumors showed increased APOBEC-signature mutations and expression of APOBEC3 region transcripts compared to patients with lesser mutational heterogeneity. TP53 mutation status was associated with APOBEC hypermutators in our cohort and in three independent LUAD datasets. In a thymic carcinoma patient, extreme heterogeneity and increased APOBEC3AB expression was associated with a high-risk germline APOBEC3AB variant allele. Patients with CNA occurring late in tumor evolution had corresponding changes in gene expression and protein abundance indicating genomic instability as a mechanism of downstream transcriptomic and proteomic heterogeneity between metastases. Across all tumors, proteomic heterogeneity was greater than copy number and transcriptomic heterogeneity. Enrichment of interferon pathways was evident both in the transcriptome and proteome of the tumors enriched for APOBEC mutagenesis despite a heterogeneous immune microenvironment across metastases suggesting a role for the immune microenvironment in the expression of APOBEC transcripts and generation of mutational heterogeneity. The evolving, heterogeneous nature of LUAD and TC, through APOBEC-mutagenesis and CNA illustrate the challenges facing treatment outcomes.

cancer biology↗