Biology subjects

Ethell, A.

Publications and source records attributed to Ethell, A..

3 recordsLinked to original sources

bioRxiv2026

Guanine content in the CTCF motif encodes a vulnerability to persistent, alcohol-induced redistribution

Alcohol consumption is a leading contributor to the global disease burden, yet its molecular consequences remain incompletely understood. Ethanols first metabolite, acetaldehyde, modifies guanine to form DNA adducts and DNA-protein crosslinks that block elongating RNA polymerase II. Because acetaldehyde acts specifically on guanine, we hypothesized that chromatin features would be disrupted in a sequence-dependent rather than stochastic manner. Here we confirm that alcohol exposure displaces elongating RNA polymerase II (RNAPIIs2p) from gene bodies, relocating to promoters. In addition to this confirmation, we found that RNAPIIs2p also relocates to discrete guanine-rich intergenic CTCF sites. Loci with high guanine content at the CTCF motifs zinc finger 5 (ZF5) binding position showed the largest increase in both CTCF and cohesin (RAD21), with CTCF occupancy changes persisting even six days after alcohol withdrawal. Surprisingly, using Hi-C, we found that these changes to CTCF and cohesin do not impact the pronounced structural CTCF loops, but are instead primarily associated with altered guanine-rich enhancer-promoter contacts that connect to lasting changes to gene expression. Beyond our cell-line model, the same sequence rule accounts for altered CTCF occupancy in a mouse starvation (metabolic stress) model and in the placentae after paternal alcohol exposure. Together these findings link alcohol exposure to sequence-directed changes to chromatin whose rules are conserved in alcohol-associated disease.

molecular biology↗

bioRxiv2025

The Splicing Factor PTBP1 interacts with RUNX1 and is Required for Leukemia Cell Survival

Runt-related Transcription Factor 1 (RUNX1) is essential for definitive hematopoiesis and is among the most frequently mutated genes in leukemia. Previous work from our lab demonstrated that Histone Deacetylase 1 (HDAC1), a known RUNX1 partner, is unexpectedly required for active transcription suggesting a non-histone role for HDAC1 regulating components of the RUNX1 complex. Here, we use proteomics, genomics, and long-read transcriptomics to identify novel RUNX1 interacting partners and decipher their role in gene regulation and RNA splicing in leukemia cells. We demonstrate that Polypyrimidine Tract Binding Protein 1 (PTBP1) interacts with RUNX1 in an HDAC1 dependent manner. Chromatin profiling revealed extensive genome-wide overlap in sites occupied by RUNX1 and PTBP1, with significant enrichment at promoters of actively transcribed genes. Loss of PTBP1 in AML cells led to widespread alterations in RNA splicing and decreased expression of genes whose promoters are bound by both factors, including metabolic genes. In agreement with these findings, we found that loss of PTBP1 reduced glycolysis and glucose uptake and ultimately caused cell death. Based on our data, we propose that the interaction between RUNX1 and PTBP1 facilitates expression of metabolic proteins essential for leukemia cell growth and survival. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/654547v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@74e3b9org.highwire.dtl.DTLVardef@12a090org.highwire.dtl.DTLVardef@eb5a48org.highwire.dtl.DTLVardef@17465dc_HPS_FORMAT_FIGEXP M_FIG C_FIG KEY POINTSO_LIPTBP1 binds RUNX1 in a HDAC1-dependent manner and co-localizes to the promoters of target genes in leukemia cells. C_LIO_LILoss of PTBP1 decreases expression of key metabolic genes, resulting in decreased cell growth and glycolysis, increased sensitivity to chemotherapy, and cell death. C_LI

cancer biology↗

bioRxiv2021

Binary outcomes of enhancer activity underlie stable random monoallelic expression

Mitotically stable random monoallelic gene expression (RME) is documented for a small percentage of autosomal genes. Here we investigated the role of enhancers in the RME of natural killer (NK) cell receptor genes. Enhancers were accessible and enriched in H3K27ac on silent and active alleles alike, decoupling enhancer activation and expression. Enhancers controlled gene expression frequency, as predicted by the binary model of enhancer action, and enhancer deletion converted the broadly expressed Nkg2d into an RME gene, recapitulating natural variegation. The results suggested that RME is a consequence of general enhancer properties and therefore many genes may be subject to some degree of RME, which was borne out by analysis of a panel of genes previously thought to be universally expressed within defined hematopoietic lineages: Nkg2d, Cd45, Cd8a and Thy1. We propose that previously documented RME is an extreme on a continuum of intrinsically probabilistic gene expression.

molecular biology↗