Biology subjects

Donmez, O. A.

Publications and source records attributed to Donmez, O. A..

3 recordsLinked to original sources

bioRxiv2025

Global Evaluation of Congenital Heart Disease-Associated Non-Coding Variants

Abstract (Summary)Genome-wide association studies (GWAS) have mapped thousands of congenital heart disease (CHD)-associated variants within non-coding regions of the genome. Non-coding variants can alter regulatory mechanisms, such as transcription factor (TF) binding control of gene expression, potentially contributing human diseases. However, with the increasing number of disease-associated variants, comprehensive functional validation remains a significant challenge. In this work, we developed a novel method called SNP Bind-n-Seq to evaluate >3,000 CHD-risk variants for allelic binding for the cardiac TFs NKX2-5, GATA4, and TBX5 in a high-throughput manner. These binding affinity data sets were coupled with a massively parallel reporter assay (MPRA) to screen CHD-risk variant genotype-dependent regulatory activity. We identified 170 variants that exhibit allelic TF binding and 187 that modulate gene expression. Combining both approaches revealed three high-confidence variants with genotype-dependent TF binding, genotype-dependent transcriptional activity, and eQTL behavior in cardiac cells. Collectively, this study provides the first combined high-throughput biochemical and functional genomic evaluation of thousands of CHD-risk variants. HighlightsO_LIAllelic binding affinity measurements of [~]9,600 variants for NKX2-5, GATA4, and TBX5 C_LIO_LIEvaluaFon of >3,000 CHD-risk variants for genotype-dependent regulatory acFvity C_LIO_LIInteracFon networks idenFfy funcFonal variants and genes involving cardiac eQTLs C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/691900v2_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1f2dc96org.highwire.dtl.DTLVardef@1700929org.highwire.dtl.DTLVardef@696ec4org.highwire.dtl.DTLVardef@1e724d8_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Human cytomegalovirus extensively re-organizes the human genome, diminishing TEAD1 transcription factor activity

Human cytomegalovirus (HCMV) infects up to 80% of the worlds population. Here, we show that HCMV infection leads to widespread changes in human chromatin accessibility and chromatin looping, with hundreds of thousands of genomic regions affected 48 hours after infection. Integrative analyses reveal HCMV-induced perturbation of Hippo signaling through drastic reduction of TEAD1 transcription factor activity. We confirm extensive concordant loss of TEAD1 binding, active H3K27ac histone marks, and chromatin looping interactions upon infection. Our data position TEAD1 at the top of a hierarchy involving multiple altered important developmental pathways. HCMV infection reduces TEAD1 activity through four distinct mechanisms: closing of TEAD1-bound chromatin, reduction of YAP1 and phosphorylated YAP1 levels, reduction of TEAD1 transcript and protein levels, and alteration of TEAD1 exon-6 usage. Altered TEAD1-based mechanisms are highly enriched at genetic risk loci associated with eye and ear development, providing mechanistic insight into HCMVs established roles in these processes.

genomics↗

bioRxiv2023

Macrophage epigenetic memories of early life injury drive neonatal nociceptive priming

The developing peripheral nervous and immune systems are functionally distinct from adults. These systems are vulnerable to early life injury, which influences outcomes related to nociception following subsequent injury later in life (i.e., "neonatal nociceptive priming"). The underpinnings of this phenomenon are largely unknown, although previous work indicates that macrophages are epigenetically trained by inflammation and injury. We found that macrophages are both necessary and partially sufficient to drive neonatal nociceptive priming possibly due to a long-lasting epigenetic remodeling. The p75 neurotrophic factor receptor (NTR) was an important effector in regulating neonatal nociceptive priming through modulation of the inflammatory profile of rodent and human macrophages. This "pain memory" was long lasting in females and could be transferred to a naive host to alter sex-specific pain-related behaviors. This study reveals a novel mechanism by which acute, neonatal post-surgical pain drives a peripheral immune-related predisposition to persistent pain following a subsequent injury. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/528015v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@117ad6eorg.highwire.dtl.DTLVardef@17b4188org.highwire.dtl.DTLVardef@10b4d9borg.highwire.dtl.DTLVardef@1142094_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗