Biology subjects

To, S. K.

Publications and source records attributed to To, S. K..

3 recordsLinked to original sources

bioRxiv2025

XIST Drives X-Chromosome Inactivation and Safeguards Female Extraembryonic Cells in Humans

Dosage compensation of sex chromosomes through X-chromosome inactivation (XCI) is required for mice extra-embryonic tissue growth and embryo development. The species specificity in mechanisms and timing leading to XCI during early embryogenesis, however, left the key question of the interdependence between XCI and human development open. Here, we show that the differentiation of naive human pluripotent stem cells to trophoblast stem cells and extraembryonic mesoderm cells triggers XCI. The inactive X chromosome, however, displays an atypical chromatin state, lacking classical enrichment of heterochromatin markers and DNA methylation. We demonstrate that extraembryonic differentiation and XCI are kinetically and functionally linked. Using loss of function approaches, we prove that XIST is required for human XCI establishment. We also reveal that XCI is key for the survival of human female extraembryonic cells. Our work therefore links XCI to the formation of extraembryonic annexes, with important consequences for human reproductive biology. HIGHLIGHTSO_LINaive hPSCs to EXMCs and TSCs differentiation recapitulates human XCI C_LIO_LIThe Xi has an unusual chromatin status in human extraembryonic cells C_LIO_LIXIST is required for the establishment of human XCI C_LIO_LIXCI supports healthy development of human female extraembryonic cells C_LI

developmental biology↗

bioRxiv2020

Defining totipotency using criteria of increasing stringency

Totipotency is the ability of a single cell to give rise to all the differentiated cells that build the conceptus, yet how to capture this property in vitro remains incompletely understood. Defining totipotency relies upon a variety of assays of variable stringency. Here we describe criteria to define totipotency. We illustrate how distinct criteria of increasing stringency can be used to judge totipotency by evaluating candidate totipotent cell types in the mouse, including early blastomeres and expanded or extended pluripotent stem cells. Our data challenge the notion that expanded or extended pluripotent states harbor increased totipotent potential relative to conventional embryonic stem cells under in vivo conditions.

cell biology↗

bioRxiv2019

Dynamic Erasure of Random X-Chromosome Inactivation during iPSC Reprogramming

BackgroundInduction and reversal of chromatin silencing is critical for successful development, tissue homeostasis and the derivation of induced pluripotent stem cells (iPSCs). X-chromosome inactivation (XCI) and reactivation (XCR) in female cells represent chromosome-wide transitions between active and inactive chromatin states. While XCI has long been studied and provided important insights into gene regulation, the dynamics and mechanisms underlying the reversal of stable chromatin silencing of X-linked genes are much less understood. Here, we use allele-specific transcriptomic approaches to study XCR during mouse iPSC reprogramming in order to elucidate the timing and mechanisms of chromosome-wide reversal of gene silencing. ResultsWe show that XCR is hierarchical, with subsets of genes reactivating early, late and very late. Early genes are activated before the onset of late pluripotency genes activation and the complete silencing of the long non-coding RNA (lncRNA) Xist. These genes are located genomically closer to genes that escape XCI, unlike those reactivating late. Interestingly, early genes also show increased pluripotency transcription factor (TF) binding. We also reveal that histone deacetylases (HDACs) restrict XCR in reprogramming intermediates and that the severe hypoacetylation state of the Xi persists until late reprogramming stages. ConclusionsAltogether, these results reveal the timing of transcriptional activation of mono-allelically repressed genes during iPSC reprogramming, and suggest that allelic activation involves the combined action of chromatin topology, pluripotency transcription factors and chromatin regulators. These findings are important for our understanding of gene silencing, maintenance of cell identity, reprogramming and disease.

developmental biology↗