Biology subjects

Stamatoyannopoulos, J.

Publications and source records attributed to Stamatoyannopoulos, J..

4 recordsLinked to original sources

bioRxiv2025

Resolving hematopoietic stem versus progenitor cell potential in the mouse dorsal aorta by differential Runx1 +110 enhancer activity

Hematopoietic stem cells (HSCs) are important in cell-based therapies for blood-related disorders. While progress has been made in the directed differentiation of pluripotent PSCs, such cultures promote hematopoietic progenitor cells (HPCs) over HSCs. Thus, elucidating signals, factors, and markers associated with HSC versus HPC lineage development in the embryo is imperative. During mouse embryonic development, HSCs and HPCs originate from hemogenic endothelium (HE) through a process critically dependent on the transcription factor Runx1. Here, we identified a Runx1 enhancer that distinguishes emerging dorsal aorta HSCs from HPCs. Phenotypic, functional, and transcriptomic analyses of Runx1 +110 enhancer-GFP reporter (110GFP) transgenic embryos showed that 110GFP expression marks HPCs, but not the emerging HSC lineage. Comparative transcriptomics revealed a 17-gene signature associated with in vivo long-term HSC potential. Furthermore, 110GFP- preHSCs showed increased expression of Jarid2 and other PRC2 components, suggesting a role for epigenetic regulation in establishing the HSC fate during EHT. Finally, single-cell multiome analysis of dorsal aorta EHT identified the Runx1 +3 enhancer as preferentially accessible in preHSC and underlined the specific activity of the +110 enhancer in HPCs. Our study demonstrates the power of cell-type specific enhancer-reporter models to dissect cell fate decisions in development and provides new inroads to label and/or perturb HSC versus HPC fate decisions in vivo and in vitro.

developmental biology↗

bioRxiv2022

FORGEdb: systematic analysis of candidate causal variants to uncover target genes and mechanisms in complex traits.

The majority of disease-associated variants identified through genome-wide association studies (GWAS) are located outside of protein-coding regions and are overrepresented in sequences that regulate gene expression. Prioritizing candidate regulatory variants and potential biological mechanisms for further functional experiments, such as genome editing, can be challenging, especially in regions with a high number of variants in strong linkage disequilibrium or multiple proximal gene targets. Improved annotation of the regulatory genome can help identify promising variants and target genes for functional genomics experiments. To advance this area, we developed FORGEdb (https://forge2.altiusinstitute.org/files/forgedb.html), a web-based tool that can rapidly integrate data for individual genetic variants, providing information on associated regulatory elements, transcription factor (TF) binding sites and target genes for over 37 million variants. FORGEdb uses annotations derived from data across a wide range of biological samples to delineate the regulatory context for each variant at the cell type level. Multiple data types, such as Combined Annotation Dependent Depletion (CADD) scores, expression quantitative trait loci (eQTLs), activity-by-contact (ABC) interactions, Contextual Analysis of TF Occupancy (CATO) scores, transcription factor (TF) motifs, DNase I hotspots, histone mark ChIP-seq peaks and chromatin states, are included in FORGEdb and these annotations are integrated into a FORGEdb score to guide assessment of functional importance. In summary, FORGEdb provides an expansive and unique resource of genomic annotations and an integrated score that can be used to accelerate the translation of identified genetic loci into biological insight.

genomics↗

bioRxiv2022

A Genome Scale Transcriptional Regulatory Model of the Human Placenta

Gene regulation is essential to placental function and fetal development. We report a genome-scale transcriptional regulatory network (TRN) of the human placenta built using digital genomic footprinting and transcriptomic data. We integrated 475 transcriptomes and 12 DNase hypersensitivity datasets from placental samples to globally and quantitatively map transcription factor (TF)-target gene interactions. In an independent dataset, the TRN model predicted target gene expression with an out of sample R2 value greater than 0.25 for 74% of target genes. We performed siRNA knockdowns of 4 TFs and achieved concordance between the predicted gene targets in our TRN and differences in expression of knockdowns with an accuracy of >0.7 for 3 of the 4 TFs. Our final model contained 113,158 interactions across 391 TFs and 7,712 target genes and is publicly available. We identified six TFs which were significantly enriched as regulators for genes previously associated with preterm birth.

systems biology↗

bioRxiv2017

Positively Selected Enhancer Elements Endow Tumor Cells with MetastaticCompetence

Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic tumors in human patients as well as nearisogenic pairs of high and low lung-metastatic osteosarcoma cells. We term these regions Metastatic Variant Enhancer Loci (Met-VELs). We demonstrate that these Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster non-randomly, indicating that activity of these enhancers and their associated gene targets are positively selected. As evidence of this causal association, osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL-associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors that occupy Met-VELs, and by knockdown or functional inhibition of individual genes activated by Met-VELs, such as F3. We further show that genetic deletion of a single Met-VEL at the F3 locus blocks metastatic cell outgrowth in the lung. These findings indicate that Met-VELs and the genes they regulate play a functional role in metastasis and may be suitable targets for anti-metastatic therapies.

cancer biology↗