Biomedical subjects

Todd Evans

Publications and source records attributed to Todd Evans.

4 recordsLinked to original sources

PubMed2026

Hypoxia-activated scleraxis a mediates epicardial progenitor differentiation into a unique cardiac perivascular cell type.

The epicardium provides progenitor cells and paracrine signals essential for heart development and regeneration, yet the mechanisms regulating epicardial cell fate remain poorly understood. Here, we identify the transcription factor Scleraxis a (scxa) as a key regulator of epicardial progenitor differentiation in zebrafish. Single-cell transcriptomics, genetic lineage tracing, and cardiac injury models reveal transient scxa expression in activated epicardial progenitor cells (aEPCs) during developmental coronary angiogenesis and heart regeneration. scxa+ epicardial cells predominantly differentiate into a previously uncharacterized col18a1a+ perivascular population, termed epicardial-derived perivascular mesenchymal cells (Epi-PMCs), which is distinct from pericytes, vascular smooth muscle cells, and mammalian adventitial fibroblasts. Epi-PMCs closely associate with coronary vessels and may contribute to vascular stabilization and remodeling, potentially through collagen XVIII. Loss of scxa increases coronary vessel density. Hypoxia and Hif signaling induce scxa expression, identifying a hypoxia-responsive mechanism that promotes epicardial differentiation toward a vascular-supportive fate during heart development and regeneration.

Animals↗

PubMed2025

A chemical epigenetic tool to probe site-specific DNA-binding protein complexes.

Site-specific DNA binding by proteins is critical for regulating transcriptional activity and cell fate decision. However, identifying proteins bound to specific genomic regions (e.g., promoter or enhancer regions) remains challenging. To address this, we developed a chemical epigenetic tool, named Site-specific noncanonical amino acid-mediated capture of protein (SCOPE), incorporating a photo-crosslinking amino acid into a nuclease-deficient dCas9 mutant. Human pluripotent stem cells (hPSCs) carrying SCOPE enable the capture of proteins bound to, in theory, any genomic location, facilitating the study of the cell context-dependent DNA-protein interactions. Using SCOPE, we identified the OCT4/SOX2/CARHSP1 complex binding to the NANOG promoter to maintain pluripotency in hPSCs. During ectoderm differentiation, ZIC2 acts as a competitive inhibitor, binding the same promoter region to downregulate NANOG expression and promote differentiation. Additionally, SCOPE identified that ZNF8 binds to the distal regulatory region of OCT4 to maintain naïve pluripotency. In summary, SCOPE provides a robust system for uncovering cell context-dependent, site-specific genome regulators, offering valuable insights into gene regulation networks driving cell fate transitions.

Humans↗

PubMed2025

Enhancer remodeling by OTX2 directs specification and patterning of mammalian definitive endoderm.

The molecular mechanisms that drive essential patterning events in the mammalian embryo remain poorly understood. Analysis of transcription factor expression kinetics at peri-gastrulation stages of development suggest Otx2 as a candidate regulator of the definitive endoderm, the precursor of all gut-derived organs. Accordingly, timed OTX2 depletion in gastruloids or during directed differentiation results in abnormal definitive endoderm specification in mouse and human, characterized by altered expression of components and transcriptional targets of the canonical WNT signaling pathway, perturbed adhesion and migration programs, and de-repression of regulators of other lineages. These defects cumulate in impaired foregut formation. Mechanistically, OTX2 is required to activate a subset of endoderm-specific enhancers and to suppress select enhancers of other lineages, allowing timely exit from the primitive streak and correct specification of anterior endoderm. Our results establish OTX2 as an early gut regulator and suggest molecular principles underlying spatiotemporal cell identity conserved across germ layers and species.

Otx Transcription Factors↗

PubMed2025

ChemPerturb-seq screen identifies a small molecule cocktail enhancing human beta cell survival after subcutaneous transplantation.

Traditional chemical screens have focused on a single assay per screen, making them labor intensive and costly. Here, we combined a chemical screen with single-cell RNA sequencing (scRNA-seq) to perform Chemical Perturb-seq (ChemPerturb-seq), enabling a systematic analysis of the molecular changes of human beta cells upon individual small molecule treatments. Using this platform, we performed an in vivo barcoded screen and discovered a small molecule cocktail, including beta-lipotropin 61-91, insulin growth factor-1, and prostaglandin E2, with which preconditioning human beta cells and primary islets significantly enhanced function and survival when transplanted subcutaneously to female, but not to male, mice. We identified two additional molecules, serotonin and histamine, that promote islet function when transplanted subcutaneously to male mice using ChemPerturb-seq. Such small molecule cocktails could be applied to improve the current FDA-approved islet transplantation procedure. Finally, we developed an artificial intelligence (AI)-powered website, ChemPerturbDB, which provides user-friendly open access analysis of the extensive ChemPerturb-seq dataset.

Humans↗