Epigenetic rejuvenation by partial reprogramming

Puri, Deepika; Wagner, Wolfgang

doi:10.1002/bies.202200208

Cited by 18 publications

(16 citation statements)

References 76 publications

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“…Our analyses suggest that this association is likely mediated by OSK stoichiometry, and may explain why sustained supraphysiological expression of the reprogramming factors is crucial for productive reprogramming. These findings not only enhance our understanding of reprogramming, but have the potential to inform research on partial reprogramming, which involves the overexpression of reprogramming factors for a short interval of time (Puri and Wagner, 2023).…”

Section: Discussionmentioning

confidence: 93%

Transcription factor stoichiometry, motif affinity and syntax regulate single-cell chromatin dynamics during fibroblast reprogramming to pluripotency

Nair,

Ameen,

Sundaram

et al. 2023

Preprint

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Ectopic expression of OCT4, SOX2, KLF4 and MYC (OSKM) transforms differentiated cells into induced pluripotent stem cells. To refine our mechanistic understanding of reprogramming, especially during the early stages, we profiled chromatin accessibility and gene expression at single-cell resolution across a densely sampled time course of human fibroblast reprogramming. Using neural networks that map DNA sequence to ATAC-seq profiles at base-resolution, we annotated cell-state-specific predictive transcription factor (TF) motif syntax in regulatory elements, inferred affinity- and concentration-dependent dynamics of Tn5-bias corrected TF footprints, linked peaks to putative target genes, and elucidated rewiring of TF-to-gene cis-regulatory networks. Our models reveal that early in reprogramming, OSK, at supraphysiological concentrations, rapidly open transient regulatory elements by occupying non-canonical low-affinity binding sites. As OSK concentration falls, the accessibility of these transient elements decays as a function of motif affinity. We find that these OSK-dependent transient elements sequester the somatic TF AP-1. This redistribution is strongly associated with the silencing of fibroblast-specific genes within individual nuclei. Together, our integrated single-cell resource and models reveal insights into the cis-regulatory code of reprogramming at unprecedented resolution, connect TF stoichiometry and motif syntax to diversification of cell fate trajectories, and provide new perspectives on the dynamics and role of transient regulatory elements in somatic silencing.

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Section: Discussionmentioning

confidence: 93%

Transcription factor stoichiometry, motif affinity and syntax regulate single-cell chromatin dynamics during fibroblast reprogramming to pluripotency

Nair,

Ameen,

Sundaram

et al. 2023

Preprint

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“…In fact, virtually all signs of cellular aging are reversed by reprogramming and are gradually reacquired upon the subsequent differentiation of iPSC-derived cells. [45,46] Derivation of cells from iPSCs is possible, and reliable protocols have been established to differentiate iPSCs toward specific cell types in 2D and into multicellular 3D organoids. [43] The need for 3D organoid cultures rather than 2D cultures was recently shown in the kidney field.…”

Section: Stem Cell Typesmentioning

confidence: 99%

Transformative Materials to Create 3D Functional Human Tissue Models In Vitro in a Reproducible Manner

Gerardo‐Nava,

Jansen,

Günther

et al. 2023

Adv Healthcare Materials

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Recreating human tissues and organs in the petri dish to establish models as tools in biomedical sciences has gained momentum. These models can provide insight into mechanisms of human physiology, disease onset, and progression, and improve drug target validation, as well as the development of new medical therapeutics. Transformative materials play an important role in this evolution, as they can be programmed to direct cell behavior and fate by controlling the activity of bioactive molecules and material properties. Using nature as an inspiration, scientists are creating materials that incorporate specific biological processes observed during human organogenesis and tissue regeneration. This article presents the reader with state‐of‐the‐art developments in the field of in vitro tissue engineering and the challenges related to the design, production, and translation of these transformative materials. Advances regarding (stem) cell sources, expansion, and differentiation, and how novel responsive materials, automated and large‐scale fabrication processes, culture conditions, in situ monitoring systems, and computer simulations are required to create functional human tissue models that are relevant and efficient for drug discovery, are described. This paper illustrates how these different technologies need to converge to generate in vitro life‐like human tissue models that provide a platform to answer health‐based scientific questions.

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“…We leveraged single-cell-nature of imaging, to get insights into the heterogeneity of reprogramming, which is of critical importance for rejuvenation 85 . We defined signature single-cells of the young and old groups and assessed the changes in the proportion of signatures in the old-OSKM group.…”

Section: Image Reveals Heterogeneity Of In Vivo Reprogramming With Os...mentioning

confidence: 99%

ImAge: an imaging approach to quantitate aging and rejuvenation

Rodriguez¹,

Fiengo²,

Alvarez-Kuglen³

et al. 2022

Preprint

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Predictive biomarkers of functional or biological age are key for evaluating interventions aimed at increas-ing healthspan and / or lifespan in humans. Currently, cardiovascular performance, blood analytes, frailty indices (e.g. gait speed), and DNA methylation clocks are used to provide such estimates; each technique has its own challenges and limitations. We have developed a novel approach, microscopic imaging of bio-logical age (miBioAge), which computes multiparametric signatures based on the patterns of epigenetic landscape in single nuclei. We demonstrated that such miBioAge readouts can robustly distinguish young and old cells from multiple tissues, reveal aging progression in peripheral blood (e.g. CD3+ T cells), and reflect changes of epigenetic signatures consistent with expected slowdown or acceleration of biological age in chronologically identical mice treated with caloric restriction or chemotherapy. Because miBioAge readouts are computed from individual samples without applying linear regression, we posit that this novel biomarker may provide personalized assessment of functional aging.

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Epigenetic rejuvenation by partial reprogramming

Cited by 18 publications

References 76 publications

Transcription factor stoichiometry, motif affinity and syntax regulate single-cell chromatin dynamics during fibroblast reprogramming to pluripotency

Transcription factor stoichiometry, motif affinity and syntax regulate single-cell chromatin dynamics during fibroblast reprogramming to pluripotency

Transformative Materials to Create 3D Functional Human Tissue Models In Vitro in a Reproducible Manner

ImAge: an imaging approach to quantitate aging and rejuvenation

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