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Transposable element activity captures human pluripotent cell states

ABSTRACT: Human pluripotent stem cells (hPSCs) exist in multiple, transcriptionally distinct states and serve as powerful models for studying human development. Despite their significance, the molecular determinants and pathways governing these pluripotent states remain incompletely understood. Here, we demonstrate that transposable elements act as sensitive indicators of distinct pluripotent cell states. We engineered hPSCs with fluorescent reporters to capture the temporal expression dynamics of two state-specific transposable elements, LTR5_Hs, and MER51B. This dual reporter system enables real-time monitoring and isolation of stem cells transitioning from naïve to primed pluripotency and further towards differentiation, serving as a more accurate readout of pluripotency states compared to conventional systems. Unexpectedly, we identified a rare, metastable cell population within primed hPSCs, marked by transcripts related to preimplantation embryo development and which is associated with a DNA damage response. Moreover, our system establishes the chromatin factor NSD1 and the RNA-binding protein FUS as potent molecular safeguards of primed pluripotency. Our study introduces a novel system for investigating cellular potency and provides key insights into the regulation of embryonic development.

SUBMITTER: Florencia Levin-Ferreyra

PROVIDER: S-SCDT-10_1038-S44319-024-00343-Y | biostudies-other |

REPOSITORIES: biostudies-other

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Transposable element activity captures human pluripotent cell states.

Project description:This SuperSeries is composed of the SubSeries listed below.

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Project description:Human pluripotent stem cells (hPSCs) serve as powerful in vitro models to elucidate the molecular underpinnings of embryonic cell fate transitions. hPSCs can be maintained in two distinct states: a naïve state, corresponding to the pre-implantation epiblast, and a primed state, mirroring the post-implantation epiblast. Our research demonstrates that transposable elements act as sensitive indicators of these pluripotency states. We engineered hPSCs with fluorescent reporters that capture the temporal expression dynamics of two transposable elements, LTR5_Hs and MER51B. This dual reporter system facilitates real-time monitoring and isolation of stem cells as they transition from naïve to primed pluripotency and further towards differentiation. Unexpectedly, we identified a rare, metastable cell population within primed hPSCs, marked by transcripts associated with pre-implantation embryo development and triggered by DNA damage. Additionally, our system uncovered novel transcriptional regulators involved in pluripotency, naïve reprogramming, and differentiation. Our study provides key insights into the dynamic regulation of transposable elements during embryonic development and introduces a novel system for investigating and exploiting cellular plasticity.

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Project description:Transposable element activity captures human pluripotent cell states.

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Transposable element sequence fragments incorporated into coding and noncoding transcripts modulate the transcriptome of human pluripotent stem cells.

Project description:Transposable elements (TEs) occupy nearly 40% of mammalian genomes and, whilst most are fragmentary and no longer capable of transposition, they can nevertheless contribute to cell function. TEs within genes transcribed by RNA polymerase II can be copied as parts of primary transcripts; however, their full contribution to mature transcript sequences remains unresolved. Here, using long and short read (LR and SR) RNA sequencing data, we show that 26% of coding and 65% of noncoding transcripts in human pluripotent stem cells (hPSCs) contain TE-derived sequences. Different TE families are incorporated into RNAs in unique patterns, with consequences to transcript structure and function. The presence of TE sequences within a transcript is correlated with TE-type specific changes in its subcellular distribution, alterations in steady-state levels and half-life, and differential association with RNA Binding Proteins (RBPs). We identify hPSC-specific incorporation of endogenous retroviruses (ERVs) and LINE:L1 into protein-coding mRNAs, which generate TE sequence-derived peptides. Finally, single cell RNA-seq reveals that hPSCs express ERV-containing transcripts, whilst differentiating subpopulations lack ERVs and express SINE and LINE-containing transcripts. Overall, our comprehensive analysis demonstrates that the incorporation of TE sequences into the RNAs of hPSCs is more widespread and has a greater impact than previously appreciated.

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