Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs

Cates, K. Lynn; McCoy, Matthew J.; Kwon, Ji-Sun; Liu, Yangjian; Abernathy, Daniel G.; Zhang, Bo; Liu, Shaopeng; Gontarz, Paul; Kim, Woo Kyung; Chen, Shawei; Kong, Wenjun; Ho, Joshua N.; Burbach, Kyle F.; Gabel, Harrison W.; Morris, Samantha A.; Yoo, Andrew S.

doi:10.1016/j.stem.2020.08.015

Cited by 53 publications

(67 citation statements)

References 84 publications

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“…[17][18][19][20] This way, 7SK provides regulatory support for fine-tuning global transcription and there is evidence that such mechanisms are implicated in neuronal differentiation. [21] The other half of 7SK core RNPs that is not associated with P-TEFb interacts with a diverse range of RNA-binding proteins (Table 1). [22][23][24] While con-siderably less is known about these 7SK subcomplexes, research over the past years has revealed that they play important roles for neuronal development and function, such as axon growth and regulation of spliceosome formation.…”

Section: Componentmentioning

confidence: 99%

“…This function of 7SK might depend on its interaction with chromatin-remodeling complexes such as the BAF complex. [20,21] A distinguishing feature of gene expression in neurons is the transcription of long genes exceeding 100 kbp in length. [34,35] The neuronal RNA-binding protein Sfpq has been identified as a critical factor in this process.…”

Section: Sk Facilitates Neuronal Gene Expressionmentioning

confidence: 99%

“…Transcription of long genes was also reduced when 7SK was knocked down during neuronal reprogramming of fibroblasts indicating that a functional 7SK/P-TEFb complex is necessary for the delivery of CDK9 to long pre-mRNAs. [21] Taking these results together, a picture emerges in which 7SK is a multi-faceted RNA that simultaneously controls not only nuclear proteins involved in gene activation and RNA processing but also cytosolic RNA-binding proteins in order to modulate subcellular RNA localization and local translation.…”

Section: Sk Facilitates Neuronal Gene Expressionmentioning

confidence: 99%

“…A recent study has dissected the reprogramming of fibroblasts into motoneurons through combined expression of microRNAs miR‐9/9* and miR‐124 and the transcription factors ISL1 and LHX3. [ 21 ] While the repression of KLF‐family transcription factors by miR‐9/9* and miR‐124 was important for erasure of the fibroblast identity, 7SK played a role for the induction of neuronal gene expression programs at later stages of differentiation. Specifically, 7SK was found to regulate the accessibility of ∼ 3,000 chromatin regions that are associated with genes required for induction of the neuronal fate.…”

Section: Sk Facilitates Neuronal Gene Expressionmentioning

confidence: 99%

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Keeping the balance: The noncoding RNA 7SK as a master regulator for neuron development and function

Briese

Sendtner

2021

BioEssays

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The noncoding RNA 7SK is a critical regulator of transcription by adjusting the activity of the kinase complex P-TEFb. Release of P-TEFb from 7SK stimulates transcription at many genes by promoting productive elongation. Conversely, P-TEFb sequestration by 7SK inhibits transcription. Recent studies have shown that 7SK functions are particularly important for neuron development and maintenance and it can thus be hypothesized that 7SK is at the center of many signaling pathways contributing to neuron function. 7SK activates neuronal gene expression programs that are key for terminal differentiation of neurons. Proteomics studies revealed a complex protein interactome of 7SK that includes several RNA-binding proteins. Some of these novel 7SK subcomplexes exert non-canonical cytosolic functions in neurons by regulating axonal mRNA transport and fine-tuning spliceosome production in response to transcription alterations. Thus, a picture emerges according to which 7SK acts as a multi-functional RNA scaffold that is integral for neuron homeostasis. K E Y W O R D S7SK, heterogeneous nuclear ribonucleoprotein (hnRNP), positive transcription elongation factor b (P-TEFb), survival motor neuron (SMN) This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Componentmentioning

confidence: 99%

Section: Sk Facilitates Neuronal Gene Expressionmentioning

confidence: 99%

Section: Sk Facilitates Neuronal Gene Expressionmentioning

confidence: 99%

Section: Sk Facilitates Neuronal Gene Expressionmentioning

confidence: 99%

See 2 more Smart Citations

Keeping the balance: The noncoding RNA 7SK as a master regulator for neuron development and function

Briese

Sendtner

2021

BioEssays

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“…Direct reprogramming of fibroblasts has been well studied over the years and proven successful in producing a variety of subtypespecific neurons. Many direct reprogramming techniques using fibroblasts have been described in detail in other reviews (Traxler et al, 2019;Cates et al, 2021;Herdy et al, 2021). The use of other cell types is important because of the advantages they possess to better reprogram into and model the desired cellular subtype as well as the need to target various resident cell types in the target tissue.…”

Section: Fibroblastsmentioning

confidence: 99%

Induced Neurons for Disease Modeling and Repair: A Focus on Non-fibroblastic Cell Sources in Direct Reprogramming

Kim

Thaqi

Peterson

et al. 2021

Front. Bioeng. Biotechnol.

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Direct cellular reprogramming exhibits distinct advantages over reprogramming from an induced pluripotent stem cell intermediate. These include a reduced risk of tumorigenesis and the likely preservation of epigenetic data. In vitro direct reprogramming approaches primarily aim to model the pathophysiological development of neurological disease and identify therapeutic targets, while in vivo direct reprogramming aims to develop treatments for various neurological disorders, including cerebral injury and cancer. In both approaches, there is progress toward developing increased control of subtype-specific production of induced neurons. A majority of research primarily utilizes fibroblasts as the donor cells. However, there are a variety of other somatic cell types that have demonstrated the potential for reprogramming into induced neurons. This review highlights studies that utilize non-fibroblastic cell sources for reprogramming, such as astrocytes, olfactory ensheathing cells, peripheral blood cells, Müller glia, and more. We will examine benefits and obstructions for translation into therapeutics or disease modeling, as well as efficiency of the conversion. A summary of donor cells, induced neuron types, and methods of induction is also provided.

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Epigenetic Dynamics in Reprogramming to Dopaminergic Neurons for Parkinson's Disease

Cho,

Kim,

Kim

et al. 2024

Advanced Science

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Direct lineage reprogramming into dopaminergic (DA) neurons holds great promise for the more effective production of DA neurons, offering potential therapeutic benefits for conditions such as Parkinson's disease. However, the reprogramming pathway for fully reprogrammed DA neurons remains largely unclear, resulting in immature and dead‐end states with low efficiency. In this study, using single‐cell RNA sequencing, the trajectory of reprogramming DA neurons at multiple time points, identifying a continuous pathway for their reprogramming is analyzed. It is identified that intermediate cell populations are crucial for resetting host cell fate during early DA neuronal reprogramming. Further, longitudinal dissection uncovered two distinct trajectories: one leading to successful reprogramming and the other to a dead end. Notably, Arid4b, a histone modifier, as a crucial regulator at this branch point, essential for the successful trajectory and acquisition of mature dopaminergic neuronal identity is identified. Consistently, overexpressing Arid4b in the DA neuronal reprogramming process increases the yield of iDA neurons and effectively reverses the disease phenotypes observed in the PD mouse brain. Thus, gaining insights into the cellular trajectory holds significant importance for devising regenerative medicine strategies, particularly in the context of addressing neurodegenerative disorders like Parkinson's disease.

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Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs

Cited by 53 publications

References 84 publications

Keeping the balance: The noncoding RNA 7SK as a master regulator for neuron development and function

Keeping the balance: The noncoding RNA 7SK as a master regulator for neuron development and function

Induced Neurons for Disease Modeling and Repair: A Focus on Non-fibroblastic Cell Sources in Direct Reprogramming

Epigenetic Dynamics in Reprogramming to Dopaminergic Neurons for Parkinson's Disease

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