Biology subjects

Williams, R. A.

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

6 recordsLinked to original sources

bioRxiv2026

Integrating epigenomic features reveals principles of chromatin-state organization

The coordinated activities of histone modifications and chromatin-associated proteins establish chromatin states that regulate genome function and cellular identity. However, the organizational principles that distinguish chromatin states across cell types remain incompletely understood. Here, we integrated genome-wide profiles of CTCF, H3K27ac, H3K9ac, H3K27me3, and H3K9me3 at 1-kb resolution to generate a unified representation of chromatin organization in human cells. Unsupervised embedding resolved five principal chromatin states corresponding to constitutive heterochromatin, CTCF-associated architectural chromatin, transcriptionally active chromatin, mixed repressive chromatin, and Polycomb-associated chromatin. Comparative analyses of HCT116 and K562 cells revealed that cell-type-specific epigenomic differences arise predominantly through remodeling of Polycomb-associated chromatin, whereas the remaining chromatin states exhibit broadly similar epigenomic signatures and comparatively limited remodeling. Consistent with this observation, principal component analysis identified H3K27me3 as the primary contributor to genome-wide epigenomic divergence, whereas CTCF represented a secondary contributor. Integration with Hi-C data further demonstrated that CTCF-associated chromatin is strongly enriched at chromatin loop anchors and other local architectural features, linking chromatin-state organization to three-dimensional genome architecture. Together, our findings identify distinct chromatin-state classes that organize the human epigenome and reveal Polycomb-associated chromatin as a key determinant of cell-type-specific epigenomic differences.

genomics↗

bioRxiv2026

Cohesin residence time gates 3D genome response to histone hyperacetylation

Cohesin-mediated loop extrusion and chromatin state-dependent compartmentalization are major drivers of three-dimensional (3D) genome organization. Although epigenomic perturbations are widely assumed to reshape chromatin architecture, the mechanisms that determine how changes in chromatin state are translated into structural reorganization remain poorly understood. Here, we identify cohesin residence time as a key regulator of the genomes architectural response to histone hyperacetylation induced by histone deacetylase inhibition (HDACi). Acute depletion of RAD21 or CTCF weakens chromatin loops but preserves HDACi-induced changes in compartmentalization, contact-scaling behavior, and loop density. In contrast, perturbation of cohesin loading or release produces opposing effects: NIPBL depletion sensitizes and amplifies architectural responses to HDACi, whereas WAPL loss renders the genome largely refractory to HDACi-induced remodeling, suppressing changes in compartments and loop density while stabilizing CTCF-anchored loops. These distinct architectural outcomes occur despite comparable levels of HDACi-induced histone hyperacetylation across genotypes, indicating that differential epigenomic input is not responsible for the observed effects. Together, our findings demonstrate that dynamic cohesin turnover, rather than cohesin chromatin association alone, governs whether epigenomic perturbations are converted into higher-order genome reorganization. These results establish cohesin residence time as a molecular gate linking chromatin state to 3D genome architecture and reveal a previously unrecognized principle underlying chromatin architecture plasticity.

genomics↗

bioRxiv2024

A Dynamic Programming Approach for the Alignment of Molecules

I.There is a need for computational approaches to compare molecules based upon chemical similarity or for evaluating biochemical transformations. Here, a new approach to molecular alignment in the Simplified Molecular Input Line Entry System (SMILES) format is introduced. Leveraging dynamic programming and scoring alignments to minimize differences in a measure of electronegativity, the study addresses the challenge of comprehending structural transformations in reaction pathways, notably transitions from linear to cyclical structures. The method is built from the Needleman-Wunsch algorithm for sequence alignment, but with a modified scoring function for different input data. Validation against a benchmarked dataset from the Krebs cycle based upon known chemical mechanisms of molecular transformations confirmed the efficacy of the approach. The transformations of the Pentose Phosphate Pathway were quantified using this algorithm and was compared with Glycolysis. The study introduces an algorithm that quantifies molecular transformations in metabolic pathways, highlighting a midpoint dissimilarity peak in cyclical pathways and a progressive decrease in molecular similarity in linear pathways. The software is available at: https://github.com/rwills5042/SMILES_Alignment.

bioinformatics↗

bioRxiv2022

Circular RNA ROR B; regulates TGFBR1 by decoying miR-140 in alcohol-exposed lungs and fibroblasts

Alcohol ingestion exaggerates transforming growth factor-beta 1 (TGF{beta}1) expression and signaling leading to fibroproliferation. Inhibition of TGF{beta} receptor type 1 (TGF{beta}R1) mitigates the effect of TGF{beta}1 signaling. We showed that alcohol can modulate microRNA (miRNA) expressions. The mechanism by which alcohol modulates microRNA and how it ties to TGF{beta}1 signaling has not been well elucidated. Circular RNA (circRNAs or circ) emerges as a potential therapeutic target based on its stability, tissue specificity, and its ability to modify miRNAs. In this study, we showed that alcohol upregulates TGF{beta}R1 and circRNA form of retinoic acid receptor-related orphan receptor beta (circ-ROR{beta}) in lung fibroblasts (LF) and the lung. We identified miR-140 to have binding sites for both TGF{beta}R1 3 UTR and circ-ROR{beta} and alcohol attenuated miR-140 expression in LF and the lung. We demonstrated that inhibition of circ-ROR{beta} upregulated miR-140 and completely abrogated alcohol-induced miR-140 suppression. We further showed that inhibition of circ-ROR{beta} attenuated alcohol-induced TGF{beta}R1, fibronectin (FN1), and -smooth muscle actin (SMA) expressions and myofibroblast development as seen by an attenuation of SMA stress fiber formation in LF. Taken together, these findings identify circ-ROR{beta}-miR-140-TGF{beta}R1 axis as a novel mechanism by which alcohol induces TGF{beta}1 signaling and promotes FMD. HighlightsAlcohol induces circ-ROR{beta} expression in lung fibroblasts Circ-ROR{beta} regulates TGF{beta}R1 by decoying miR-140 in lung fibroblasts Inhibition of Circ-ROR{beta} restores miR-140 expression Inhibition of Circ-ROR{beta} mitigates alcohol-mediated myofibroblast differentiation This is the first description of circ-ROR{beta} functional significance in lung fibroblast

physiology↗

bioRxiv2022

A common human brain-derived neurotrophic factor polymorphism leads to sustained depression of excitatory synaptic transmission by isoflurane in hippocampus

Multiple presynaptic and postsynaptic targets have been identified for the reversible neurophysiological effects of general anesthetics on synaptic transmission and neuronal excitability. However, the synaptic mechanisms involved in persistent depression of synaptic transmission resulting in more prolonged neurological dysfunction following anesthesia are less clear. Here, we show that brain-derived neurotrophic factor (BDNF), a growth factor implicated in synaptic plasticity and dysfunction, enhances glutamate synaptic vesicle exocytosis, and that attenuation of vesicular BDNF release by isoflurane contributes to transient depression of excitatory synaptic transmission in mice. This reduction in synaptic vesicle exocytosis was irreversible in neurons that release less endogenous BDNF due to a polymorphism (BDNF Val66Met) compared to wild-type mouse hippocampal neurons following isoflurane exposure. These effects were prevented by exogenous application of BDNF. Our findings identify a role for a common human BDNF single nucleotide polymorphism (Val66Met; rs6265) in persistent changes of synaptic function following isoflurane exposure. These persistent alterations in excitatory synaptic transmission have important implications for the role of genotype in anesthetic effects on synaptic plasticity and neurocognitive function.

neuroscience↗

bioRxiv2021

Cholecystokinin Suppresses β-Cell Apoptosis, Including in Human Islets in a Transplant Model

Loss of functional pancreatic {beta}-cell mass and increased {beta}-cell apoptosis are fundamental to the pathophysiology of both type 1 and type 2 diabetes. Pancreatic islet transplantation has the potential to cure type 1 diabetes but is often ineffective due to the death of the islet graft within the first few years after transplant. Therapeutic strategies to directly target pancreatic {beta}-cell survival are needed to prevent and treat diabetes and to improve islet transplant outcomes. Reducing {beta}-cell apoptosis is also a therapeutic strategy for type 2 diabetes. Cholecystokinin (CCK) is a peptide hormone typically produced in the gut after food intake, with positive effects on obesity and glucose metabolism in mouse models and human subjects. We have previously shown that pancreatic islets also produce CCK. The production of CCK within the islet promotes {beta}-cell survival in rodent models of diabetes and aging. Now, we demonstrate a direct effect of CCK to reduce cytokine-mediated apoptosis in a {beta}-cell line and in isolated mouse islets in a receptor-dependent manner. However, whether CCK can protect human {beta}-cells was previously unknown. Here, we report that CCK can also reduce cytokine-mediated apoptosis in isolated human islets and CCK treatment in vivo decreases {beta}-cell apoptosis in human islets transplanted into the kidney capsule of diabetic NOD/SCID mice. Collectively, these data identify CCK as a novel therapy that can directly promote {beta}-cell survival in human islets and has therapeutic potential to preserve {beta}-cell mass in diabetes and as an adjunct therapy after transplant. One Sentence SummaryCholecystokinin ameliorates pancreatic {beta}-cell death under models of stress and after transplant of human islets.

cell biology↗