An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair

Yan, Ruorong; Cigliola, Valentina; Oonk, Kelsey A.; Petrover, Zachary; DeLuca, Sophia; Wolfson, David; Vekstein, Andrew M.; Mendiola, Michelle; Devlin, Garth; Bishawi, Muath; Gemberling, Matthew; Sinha, Tanvi; Sargent, Michelle A.; York, Allen J.; Shakked, Avraham; DeBenedittis, Paige; Wendell, David C.; Ou, Jianhong; Kang, Junsu; Goldman, Joseph D.; Baht, Gurpreet S.; Karra, Ravi; Williams, Adam R.; Bowles, Dawn E.; Asokan, Aravind; Tzahor, Eldad; Gersbach, Charles A.; Molkentin, Jeffery D; Bursac, Nenad; Black, Brian L.; Poss, Kenneth D.

doi:10.1016/j.stem.2022.11.012

Cited by 31 publications

(21 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One such promising tool is the RRE or tissue-regeneration enhancer elements that can confer spatial or temporal control of key regeneration genes (Kang et al 2016 ). A new study from the Poss group demonstrated that zebrafish RREs were sufficient to stimulate or suppress endogenous gene expression after ischemic myocardial infarction in mice (Yan et al 2023 ). Interestingly, a constitutively active YAP factor driven by such tool was sufficient to promote cardiac regeneration in mice, resulting in improved function of the injured heart (Yan et al 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Regulation of chromatin organization during animal regeneration

2023

View full text Add to dashboard Cite

Activation of regeneration upon tissue damages requires the activation of many developmental genes responsible for cell proliferation, migration, differentiation, and tissue patterning. Ample evidence revealed that the regulation of chromatin organization functions as a crucial mechanism for establishing and maintaining cellular identity through precise control of gene transcription. The alteration of chromatin organization can lead to changes in chromatin accessibility and/or enhancer-promoter interactions. Like embryogenesis, each stage of tissue regeneration is accompanied by dynamic changes of chromatin organization in regeneration-responsive cells. In the past decade, many studies have been conducted to investigate the contribution of chromatin organization during regeneration in various tissues, organs, and organisms. A collection of chromatin regulators were demonstrated to play critical roles in regeneration. In this review, we will summarize the progress in the understanding of chromatin organization during regeneration in different research organisms and discuss potential common mechanisms responsible for the activation of regeneration response program.

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of chromatin organization during animal regeneration

2023

View full text Add to dashboard Cite

show abstract

“…Interestingly, REN:GFP reporter expression was tied between these two domains, almost perfectly anti-correlated with one another up to 30 days into regeneration after muscle has regrown. Transcriptional enhancers for regeneration have been characterized to signal between organs during regeneration underlie evolution of regenerative capacity and used as tools to deliver pro-regenerative molecules in mammals (Sun et al, 2022; Wang et al, 2020; Yan et al, 2022; Zlatanova et al, 2023). However, mechanisms for how regenerative enhancers are recruited and targeted to critical genes are unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Expression of ankdr1a , also known as CARP, increases 52.82-fold in Δ REN mutants but only 12.96-fold in wildtype regeneration. An enhancer for CARP called 2ankrd1aEN was found together with REN using H3.3 profiling and 2ankrd1aEN can drive gene expression at the site of injury in both mouse and porcine hearts (Yan et al, 2022). For example, anln which encodes a protein required for cytokinesis (increased 6.19–fold in Δ REN mutants, increased 2.41–fold in wildtype, residual = 1.72)(Oegema et al, 2000; Takayama et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

A Cardiac Transcriptional Enhancer is Repurposed During Regeneration to Activate an Anti-proliferative Program

Rao,

Russell,

Segura-Bermudez

et al. 2023

Preprint

View full text Add to dashboard Cite

Previously, we discovered a gene regulatory element, called103runx1EN(or REN), capable of activating target gene expression throughout the heart during regeneration. REN also drives expression in uninjured cardiac tissue surrounding valves viewed from the reporter and phenotypes arising from a REN-deletion mutant. Activity of the REN reporter peaks just before and during the peak of regeneration. During this time, REN activity in myocardium adjacent to the valves goes away. The expression dynamics of the REN reporter, motifs embedded within REN and the fact that REN activates not just during injury but generally during cardiomyocyte proliferation all suggest that REN is an enhancer promoting regeneration. Unexpectedly, deletion ofRENresults in improved cardiomyocyte proliferation suggesting activation of anti-proliferative factors is part of the normal course of regeneration. REN is also active in the newly formed regenerated muscle during the conclusion of regeneration. Taken together, our findings support a model that in the zebrafish heart, an anti-proliferative gene expression program controls the spatiotemporal dynamics of cardiomyocyte proliferation.

show abstract

“…3J), highlighting the genomic co-occupancy of AP-1/Tead and AP-1/Stat in aEpi/aFBs and aECs, respectively. The differential OCRs of the activated nonCMs showed a subtantial overlap with recently identified tissue regeneration enhancer elements (TREEs) that directed gene expression in injury sites (table S2), including the LEN element that was engineered to stimulate cardiac regeneration (21)(22)(23)(24). We then determined whether other activated nonCM's OCRs are functional in driving gene expression in injury sites.…”

Section: Major Noncm Cell Types Exhibit Heterogeneity Of Chromatin Ac...mentioning

confidence: 95%

Single-cell chromatin profiling reveals genetic programs activating proregenerative states in nonmyocyte cells

Dong,

Yang,

Wang

et al. 2024

Sci. Adv.

View full text Add to dashboard Cite

Cardiac regeneration requires coordinated participation of multiple cell types whereby their communications result in transient activation of proregenerative cell states. Although the molecular characteristics and lineage origins of these activated cell states and their contribution to cardiac regeneration have been studied, the extracellular signaling and the intrinsic genetic program underlying the activation of the transient functional cell states remain largely unexplored. In this study, we delineated the chromatin landscapes of the noncardiomyocytes (nonCMs) of the regenerating heart at the single-cell level and inferred the cis-regulatory architectures and trans-acting factors that control cell type–specific gene expression programs. Moreover, further motif analysis and cell-specific genetic manipulations suggest that the macrophage-derived inflammatory signal tumor necrosis factor–α, acting via its downstream transcription factor complex activator protein–1, functions cooperatively with discrete transcription regulators to activate respective nonCM cell types critical for cardiac regeneration. Thus, our study defines the regulatory architectures and intercellular communication principles in zebrafish heart regeneration.

show abstract

An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair

Cited by 31 publications

References 72 publications

Regulation of chromatin organization during animal regeneration

Regulation of chromatin organization during animal regeneration

A Cardiac Transcriptional Enhancer is Repurposed During Regeneration to Activate an Anti-proliferative Program

Single-cell chromatin profiling reveals genetic programs activating proregenerative states in nonmyocyte cells

Contact Info

Product

Resources

About