Biology subjects

Edri, S.

Publications and source records attributed to Edri, S..

3 recordsLinked to original sources

bioRxiv2018

Histone Acetyltransferase Kat2a Stabilises Pluripotency with Control of Transcriptional Heterogeneity

Cell fate transitions in mammalian stem cell systems have often been associated with transcriptional heterogeneity, however existing data have failed to establish a functional or mechanistic link between the two phenomena. Experiments in unicellular organisms support the notion that transcriptional heterogeneity can be used to facilitate adaptability to environmental changes and have identified conserved chromatin-associated factors that modulate levels of transcriptional noise. Herein, we show destabilisation of pluripotency-associated gene regulatory networks through increased transcriptional heterogeneity of mouse embryonic stem cells in which paradigmatic histone acetyl-transferase, and candidate noise modulator, Kat2a (yeast orthologue Gcn5) has been inhibited. Functionally, network destabilisation associates with reduced pluripotency and accelerated mesendodermal differentiation, with increased probability of transitions into lineage commitment. Thus, we functionally link transcriptional heterogeneity to cell fate transitions through manipulation of the histone acetylation landscape of mouse embryonic stem cells and establish a general paradigm that could be exploited in other normal and malignant stem cell fate transitions.

developmental biology↗

bioRxiv2018

Emergence of a node-like population within an in vitro derived Neural Mesodermal Progenitors (NMPs) population

The mammalian embryos Caudal Lateral Epiblast (CLE) harbours bipotent progenitors, called Neural Mesodermal Progenitors (NMPs), that contribute to the spinal cord and the paraxial mesoderm throughout axial elongation. Here we performed a single cell analysis of different in vitro NMPs populations produced either from embryonic stem cells (ESCs) or epiblast stem cells (EpiSCs) and compared them to E8.25 CLE mouse embryos. In our analysis of this region our findings challenge the notion that NMPs should coexpress Sox2 and T. We built a Support Vector Machine (SVM) based on the embryo CLE and use it as a classification model to analyse the in vitro NMP-like populations. We showed that ESCs derived NMPs are heterogeneous and contain few NMP-like cells, whereas EpiSCs derived NMPs, produce a high proportion of cells with the embryo NMP signature. Importantly, we found that the population from which the Epi-NMPs are derived in culture, contains a nodelike population, which is responsible for maintaining the expression of T in vitro. These results mimic the events in vivo and suggest a sequence of events for the NMPs emergence.

developmental biology↗

bioRxiv2018

An Epiblast Stem Cell derived multipotent progenitor population for axial extension

The Caudal Lateral Epiblast of mammalian embryos harbours bipotent progenitors that contribute to the spinal cord and the paraxial mesoderm in concert with the elongation of the body axis. These progenitors, called Neural Mesodermal Progenitors (NMPs) are identified as cells coexpressing Sox2 and T/Brachyury, a criterion used to derive NMP-like cells from Embryonic Stem Cells in vitro. However, these progenitors do not self renew, as embryonic NMPs do. Here we find that protocols that yield NMP-like cells in vitro first produce a multipotent population that, additional to NMPs, generates progenitors for the lateral plate and intermediate mesoderm. We show that Epiblast Stem Cells (EpiSCs) are an effective source for these multipotent progenitors that are further differentiated by a balance between BMP and Nodal signalling. Importantly, we show that NMP-like cells derived from EpiSCs self renew in vitro and exhibit a gene expression signature similar to that of their embryo counterparts.

developmental biology↗