Biology subjects

Ullate-Agote, A.

Publications and source records attributed to Ullate-Agote, A..

3 recordsLinked to original sources

bioRxiv2022

Revealing cell populations catching the early stages of the human embryo development in naive pluripotent stem cells

Naive human pluripotent stem cells (hPSCs) are defined as the in vitro counterpart of the human preimplantation embryos epiblast and are used as a model system to study developmental processes. In this study, we report the discovery and characterization of distinct cell populations coexisting with epiblast-like cells in 5iLAF naive human induced PSCs (hiPSCs) cultures. Noteworthily these populations closely resemble different cell types of the human embryo at early developmental stages. While epiblast-like cells represented the main cell population, interestingly we detected a cell population with gene and transposable element expression profile closely resembling the totipotent 8-Cell (8C) stage human embryo, and three cell populations analogous to trophectoderm (TE) cells at different stages of their maturation process: transition, early and mature stage. Thus, 5iLAF naive hiPSCs cultures provide an excellent opportunity to model the earliest events of human embryogenesis, from the 8C stage to the peri-implantation period. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/482812v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@11b680eorg.highwire.dtl.DTLVardef@4c7e0forg.highwire.dtl.DTLVardef@1e84568org.highwire.dtl.DTLVardef@24ee65_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2021

A diabetic milieu increases cellular susceptibility to SARS-CoV-2 infections in engineered human kidney organoids and diabetic patients

SARS-CoV-2 infections lead to a high risk of hospitalization and mortality in diabetic patients. Why diabetic individuals are more prone to develop severe COVID-19 remains unclear. Here, we established a novel human kidney organoid model that mimics early hallmarks of diabetic nephropathy. High oscillatory glucose exposure resulted in metabolic changes, expansion of extracellular membrane components, gene expression changes determined by scRNAseq, and marked upregulation of angiotensin-converting enzyme 2 (ACE2). Upon SARS-CoV-2 infection, hyperglycemic conditions lead to markedly higher viral loads in kidney organoids compared to normoglycemia. Genetic deletion of ACE2, but not of the candidate receptor BSG/CD147, in kidney organoids demonstrated the essential role of ACE2 in SARS-CoV-2 infections and completely prevented SARS-CoV-2 infection in the diabetogenic microenvironment. These data introduce a novel organoid model for diabetic kidney disease and show that diabetic-induced ACE2 licenses the diabetic kidney to enhanced SARS-CoV-2 replication.

cell biology↗

bioRxiv2019

IMPACT OF GENOME ARCHITECTURE UPON THE FUNCTIONAL ACTIVATION AND REPRESSION OF Hox REGULATORY LANDSCAPES

BackgroundThe spatial organization of the mammalian genome relies upon the formation of chromatin domains of various scales. At the level of gene regulation in cis, collections of enhancer sequences define large regulatory landscapes that usually match with the presence of topologically associating domains (TADs). These domains are largely determined by bound CTCF molecules and often contain ranges of enhancers displaying similar or related tissue specificity, suggesting that in some cases such domains may act as coherent regulatory units, with a global on or off state.\n\nResultsBy using the HoxD gene cluster as a paradigm, we investigated the effect of large genomic rearrangements affecting the two TADs flanking this locus, including their fusion into a single chromatin domain. We show that, within a single hybrid TAD, the activation of both proximal and distal limb enhancers initially positioned in either TADs globally occurred as when both TADs are intact. We also show that the timely implementation of distal limb enhancers depends on whether or not target genes had previously responded to proximal enhancers, due to the presence or absence of H3K27me3 marks.\n\nConclusionsFrom this work, we conclude that antagonistic limb proximal and distal enhancers can exert their specificities when positioned into the same TAD and in the absence of their genuine target genes. We also conclude that removing these target genes reduced the coverage of a regulatory landscape by chromatin marks associated with silencing and thus prolonged its activity in time. Since Polycomb group proteins are mainly recruited at the Hox gene cluster, our results suggest that Polycomb Repressive Complex 2 (PRC2) can extend its coverage to far-cis regulatory sequences as long as confined to the neighboring TAD structure.

developmental biology↗