Biology subjects

Yildirim, A.

Publications and source records attributed to Yildirim, A..

9 recordsLinked to original sources

bioRxiv2025

Lipid Tail Length Determines Nano-Bio Interactions of Peptide Amphiphile Nanostructures

Understanding the interactions of nanomaterials with biological systems is essential to designing effective nanomedicines. However, most of our understanding originates from studies with solid nanoparticles, and nano-bio interactions of self-assembled nanomaterials have remained largely unexplored. To address this knowledge gap, we develop a series of self-assembling peptide amphiphiles (PAs) with different lipid modifications and investigate their interactions with biological systems. We find that PA nanostructures rapidly disassemble and reassemble with albumin and lipoproteins in blood plasma. While PAs with shorter lipid tails mainly assemble with albumin, increasing lipid length shifts binding to lipoproteins. All PAs show strong tumor accumulation in 4T1 tumor-bearing mice with tumor to liver ratios of [~]3-6. Overall, albumin-binding improves blood circulation and tumor accumulation compared to lipoprotein-binding, but also increases off-target accumulation. This study shows that the biointeractions of self-assembled nanomaterials can be controlled through molecular design, which may lead to the development of effective nanomedicines.

bioengineering↗

bioRxiv2024

Peptide Amphiphiles Hitchhike on Endogenous Biomolecules for Enhanced Cancer Imaging and Therapy

The interactions of nanomaterials with biomolecules in vivo determine their biological fate. Here, we show that self-assembled peptide amphiphile (PA) nanostructures can dynamically interact with endogenous biomolecules and take advantage of naturally occurring processes to target a broad range of solid tumors. In circulation, self-assembled PA nanostructures disassemble and reassemble mainly with lipoproteins, which prolongs blood circulation and dramatically improves tumor accumulation and retention. Mechanistic studies suggested that PAs internalize into cancer cells by assembling with their cell membranes and independently of specific receptors. By exploiting these interactions, a PA developed in this study (namely SA-E) demonstrated specific accumulation in various xenograft, syngeneic, patient-derived xenograft, or transgenic rodent models. In addition, SA-E enabled the effective delivery of highly potent chemotherapy to different syngeneic and xenografted tumors with reduced side effects. With its simple and modular design and universal tumor accumulation mechanism, SA-E represents a promising platform for broad applications in cancer imaging and therapy.

bioengineering↗

bioRxiv2023

Conformational analysis of chromosome structures reveals vital role of chromosome morphology in gene function

The 3D conformations of chromosomes are highly variant and stochastic between single cells. Recent progress in multiplexed 3D FISH imaging, single cell Hi-C and genome structure modeling allows a closer analysis of the structural variations of chromosomes between cells to infer the functional implications of structural heterogeneity. Here, we introduce a two-step dimensionality reduction method to classify a population of single cell 3D chromosome structures, either from simulation or imaging experiment, into dominant conformational clusters with distinct chromosome morphologies. We found that almost half of all structures for each chromosome can be described by 5-10 dominant chromosome morphologies, which play a fundamental role in establishing conformational variation of chromosomes. These morphologies are conserved in different cell types, but vary in their relative proportion of structures. Chromosome morphologies are distinguished by the presence or absence of characteristic chromosome territory domains, which expose some chromosomal regions to varying nuclear environments in different morphologies, such as nuclear positions and associations to nuclear speckles, lamina, and nucleoli. These observations point to distinct functional variations for the same chromosomal region in different chromosome morphologies. We validated chromosome conformational clusters and their associated subnuclear locations with data from DNA-MERFISH imaging and single cell sci-HiC data. Our method provides an important approach to assess the variation of chromosome structures between cells and link differences in conformational states with distinct gene functions.

genomics↗

bioRxiv2022

Reliability metrics of outcome measures during the single and double leg drop jump tests

Although a number of previous studies have studied reliability metrics of outcome measures during single and double leg drop jump tests, none of them presented detailed reliability information for both tests with a group of collegiate athletes of both genders. The aim of this study was therefore to assess the reliability of outcome measures during the single and double leg drop jump tests with proper reliability metrics. Seventeen handball players (11 male and 6 female) participated in the experiments. Each player performed three double leg and three single drop jumps from a 30 cm height box onto a portable force plate in two sessions a week apart. Sixteen outcome measures, including jump height (JH), ground contact time (GCT), reactive strength index (RSI), were calculated. Four groups of reliability metrics like absolute agreement and consistency intraclass correlation coefficients (inter-day and intra-day), standard error of measurement, coefficient of variation, and minimal metrically detectable change were estimated for reliability assessment. The outcome measures as RSI and its individual components JH and GCT together with normalized vertical stiffness (Kvert) yielded high inter-day and intra-day intraclass correlation coefficients and low standard error of measurement and coefficient of variation levels for the double leg drop jump test. The more challenging single leg drop jump test could also be considered reproducible with some other highly reliable outcome measure set by keeping JH, GCT, and normalized Kvert and replacing vertical jump impulse with RSI. The results of the current study therefore suggested the drop jump tests could be deemed reliable to be used for short-term and long-term monitoring needs for a group of collegiate athletes of both genders.

physiology↗

bioRxiv2022

In silico screening and testing of FDA approved small molecules to block SARS-CoV-2 entry to the host cell by inhibiting Spike protein cleavage

The COVID-19 pandemic began in 2019, but it is still active. The development of an effective vaccine reduced the number of deaths; however, a treatment is still needed. Here, we aimed to inhibit viral entry to the host cell by inhibiting Spike (S) protein cleavage by several proteases. We develop a computational pipeline to repurpose FDA-approved drugs to inhibit protease activity and thus prevent S protein cleavage. We tested some of our drug candidates and demonstrated a decrease in protease activity. We believe our pipeline will be beneficial in identifying a drug regimen for COVID-19 patients.

biophysics↗

bioRxiv2021

Genome wide profiling of histone H3 lysine 4 methylation during the Chlamydomonas cell cycle reveals stable and dynamic properties of lysine 4 trimethylation at gene promoters and near ubiquitous lysine 4 monomethylation

Chromatin modifications are key epigenetic regulatory features with roles in various cellular events, yet histone mark identification, gene wide distribution and relationship to gene expression remains understudied in green algae. Histone lysine methylation is regarded as an active chromatin mark in many organisms, and is implicated in mediating active euchromatin. We interrogated the genome wide distribution pattern of mono- and trimethylated H3K4 using Chromatin-Immunoprecipitation followed by deep-sequencing (ChIP-Seq) during key phases of the Chlamydomonas cell cycle: early G1 phase (ZT1) when cells initiate biomass accumulation, S/M phase (ZT13) when cells are undergoing DNA replication and mitosis, and late G0 phase (ZT23) when they are quiescent. Tri-methylated H3K4 was predominantly enriched at TSSs of the majority of protein coding genes (85%). The likelihood of a gene being marked by H3K4me3 correlated with it being transcribed at one or more time points during the cell cycle but not necessarily by continuous active transcription. This finding even applied to early zygotic genes whose expression may be dormant for hundreds or thousands of generations between sexual cycles; but core meiotic genes were completely missing H3K4me3 peaks at their TSS. In addition, bi-directional promoters regulating expression of replication dependent histone genes, had transient H3K4me3 peaks that were present only during S/M phase when their expression peaked. In agreement with biochemical studies, mono-methylated H3K4 was the default state for the vast majority of histones that were outside of TSS and terminator regions of genes. A small fraction of the genome which was depleted of any H3 lysine methylation was enriched for DNA cytosine methylation and the genes within these DNA methylation islands were poorly expressed. Genome wide H3K4me3 ChIP-Seq data will be a valuable resource, facilitating gene structural annotation, as exemplified by our validation of hundreds of long non-coding RNA genes.

genomics↗

bioRxiv2021

Integrative Genome Modeling Platform reveals essentialityof rare contact events in 3D genome organizations

A multitude of sequencing-based and microscopy technologies provide the means to unravel the relationship between the three-dimensional (3D) organization of genomes and key regulatory processes of genome function. However, it remains a major challenge to systematically integrate all available data sources to characterize the nuclear organization of genomes across different spatial scales. Here, we develop a multi-modal data integration approach to produce genome structures that are highly predictive for nuclear locations of genes and nuclear bodies, local chromatin compaction, and spatial segregation of functionally related chromatin. By performing a quantitative assessment of the predictive power of genome structures generated from different data combinations, we demonstrate that multimodal data integration can compensate for systematic errors and missing values in some of the data and thus, greatly increases accuracy and coverage of genome structure models. We also show that alternative combinations of different orthogonal data sources can converge to models with similar predictive power. Moreover, our study reveals the key contributions of low-frequency inter-chromosomal contacts (e.g., "rare" contact events) to accurately predicting the global nuclear architecture, including the positioning of genes and chromosomes. Overall, our results highlight the benefits of multi-modal data integration for genome structure analysis, available through the Integrative Genome structure Modeling (IGM) software package that we introduce here.

biophysics↗

bioRxiv2021

Mapping the nuclear microenvironment of genes at agenome-wide scale

The nuclear folding of chromosomes relative to nuclear bodies is an integral part of gene function. Here, we demonstrate that population-based modeling--from ensemble Hi-C data--can provide a detailed description of the nuclear microenvironment of genes and its role on gene function. We define the microenvironment by the subnuclear positions of genomic regions with respect to nuclear bodies, local chromatin compaction, and preferences in chromatin compartmentalization. These structural descriptors are determined in single cell models on a genome-wide scale, thereby revealing the structural variability between cells. We demonstrate that the structural microenvironment of a genomic region is linked to its functional potential in gene transcription, replication and chromatin compartmentalization. Some chromatin regions are distinguished by their strong preferences to a single microenvironment, due to associations to specific nuclear bodies in most cells. Other chromatin shows high structural variability, which is a strong indicator of functional heterogeneity. Moreover, we identify specialized nuclear microenvironments, which distinguish chromatin in different functional states and reveal a key role of nuclear speckles in chromosome organization. We demonstrate that our method produces highly predictive 3-dimensional genome structures, which accurately reproduce data from TSA-seq, DamID, GPSeq and super-resolution imaging. Thus, our method considerably expands the range of Hi-C data analysis and is widely applicable.

genomics↗

bioRxiv2020

SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNPs from Cajal bodies to nuclear speckles for spliceosome assembly

Splicing is catalyzed by the spliceosome, a compositionally dynamic complex assembled stepwise on pre-mRNA. We reveal links between splicing machinery components with the intrinsically disordered ciliopathy protein SANS. Pathogenic mutations in SANS/USH1G lead to Usher syndrome - the most common cause of deaf-blindness. SANS functions have been associated with cytoplasmic processes so far. Here, we reveal molecular links between SANS and pre-mRNA splicing catalyzed by the spliceosome, a compositionally dynamic complex assembled stepwise on pre-mRNA in the nucleus. Here, we show SANS associates with Cajal bodies and nuclear speckles, where SANS interacts with components of spliceosomal sub-complexes such as SF3B1 and the large splicing cofactor SON but also with PRPFs and snRNAs related to the tri-snRNP complex. SANS is required for the transfer of tri-snRNPs from Cajal bodies to nuclear speckles. SANS depletion alters the kinetics of spliceosome assembly, leading to accumulation of Complex A. SANS deficiency and USH1G pathogenic mutations affects splicing of genes related to cell proliferation and USH. Thus, we provide the first evidence that splicing deregulation may participate in the pathophysiology of Usher syndrome.

cell biology↗