Defining Human Pluripotency

Yilmaz, Atilgan; Benvenisty, Nissim

doi:10.1016/j.stem.2019.06.010

Cited by 65 publications

(53 citation statements)

References 131 publications

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“…We indeed identified a positive correlation (r = 0.57, p < 10 −16 ) between the fold-change in expression and fold-change in promoter-H3-acetylation ( Figure 3 D), and observed the expected differential acetylation in the pluripotency factors that were found differentially expressed ( Figures 2 C and 3 D). In addition, we identified the naive pluripotency factors; ZFP42 (REX1) KLF2 and KLF4 ( Kalkan and Smith, 2014 , Yilmaz and Benvenisty, 2019 ) to be hyper-acetylated, while the primed marker DUSP6 ( Messmer et al., 2019 ) was hypo-acetylated ( Figures 3 D and 3E). Overall our results suggest that ZMYM2 functions to repress a large set of germline-related genes, possibly in an HDAC1/2-mediated manner, while on the other hand it normally primes a second smaller set of genes that are related to somatic differentiation, likely as a secondary effect of the first gene set.…”

Section: Resultsmentioning

confidence: 97%

“…Human embryonic stem cells (ESCs), derived from the inner cell mass (ICM) of the pre-implantation blastocyst, have the capacity for self-renewal in culture as well as the potential to differentiate into virtually any cell type of the developing fetus ( Schuldiner et al., 2002 , Thomson et al., 1998 ). Cultured ESCs differ from their embryonic origin in several molecular characteristics ( Huang et al., 2014 , Nakamura et al., 2016 ), but in vitro resetting of human primed ESCs to a more “naive” state has been reported to closely mimic ICM-like transcriptional and epigenetic features ( Sagi and Benvenisty, 2016 , Schlesinger and Meshorer, 2019 , Theunissen et al., 2014 , Ware et al., 2014 , Weinberger et al., 2016 , Yilmaz and Benvenisty, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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The Chromatin Regulator ZMYM2 Restricts Human Pluripotent Stem Cell Growth and Is Essential for Teratoma Formation

et al. 2020

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Summary Chromatin regulators play fundamental roles in controlling pluripotency and differentiation. We examined the effect of mutations in 703 genes from nearly 70 chromatin-modifying complexes on human embryonic stem cell (ESC) growth. While the vast majority of chromatin-associated complexes are essential for ESC growth, the only complexes that conferred growth advantage upon mutation of their members, were the repressive complexes LSD-CoREST and BHC. Both complexes include the most potent growth-restricting chromatin-related protein, ZMYM2. Interestingly, while ZMYM2 expression is rather low in human blastocysts, its expression peaks in primed ESCs and is again downregulated upon differentiation. ZMYM2 -null ESCs overexpress pluripotency genes and show genome-wide promotor-localized histone H3 hyper-acetylation. These mutant cells were also refractory to differentiate in vitro and failed to produce teratomas upon injection into immunodeficient mice. Our results suggest a central role for ZMYM2 in the transcriptional regulation of the undifferentiated state and in the exit-from-pluripotency of human ESCs.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

The Chromatin Regulator ZMYM2 Restricts Human Pluripotent Stem Cell Growth and Is Essential for Teratoma Formation

et al. 2020

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“…However, there are a limited number of sources for these somatic stem cells and they exhibit a restricted capacity for differentiation ( Clevers, 2015 ). On the contrary, PSCs are relatively easy to be maintained in culture and can differentiate into essentially any cell types ( Rossant and Papaioannou, 1984 , Yilmaz and Benvenisty, 2019 ). Furthermore, genetically reprogramed iPSCs ( Takahashi et al., 2007 , Takahashi and Yamanaka, 2006 ) offer unique opportunities for personalized medicine, because the iPSCs can be derived from patients' own cells and they are resistant to immunocompatibility issues ( Johnson and Hockemeyer, 2015 , Yilmaz and Benvenisty, 2019 ).…”

Section: Main Textmentioning

confidence: 99%

Progress in Modeling and Targeting Inner Ear Disorders with Pluripotent Stem Cells

2020

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Sensorineural hearing loss and vestibular dysfunction are caused by damage to neurons and mechanosensitive hair cells, which do not regenerate to any clinically relevant extent in humans. Several protocols have been devised to direct pluripotent stem cells (PSCs) into inner ear hair cells and neurons, which display many properties of their native counterparts. The efficiency, reproducibility, and scalability of these protocols are enhanced by incorporating knowledge of inner ear development. Modeling human diseases in vitro through genetic manipulation of PSCs is already feasible, thereby permitting the elucidation of mechanistic understandings of a wide array of disease etiologies. Early studies on transplantation of PSC-derived otic progenitors have been successful in certain animal models, yet restoration of function and long-term cell survival remain unrealized. Through further research, PSC-based approaches will continue to revolutionize our understanding of inner ear biology and contribute to the development of therapeutic treatments for inner ear disorders.

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“…These protocols have been discussed in depth in a recent review (Tang et al, 2020). The PSCs and organoid technology are ideal for creating patient-specific disease models for USH, with these in vitro models possessing an identical genomic profile of the patient, offering opportunities for personalized medicine (Johnson and Hockemeyer, 2015;Yilmaz and Benvenisty, 2019).…”

Section: Stem Cells and Three-dimensional Organoidsmentioning

confidence: 99%

Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy

Whatley

Francis

et al. 2020

Front. Genet.

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Usher syndrome (USH) is an autosomal recessive (AR) disorder that permanently and severely affects the senses of hearing, vision, and balance. Three clinically distinct types of USH have been identified, decreasing in severity from Type 1 to 3, with symptoms of sensorineural hearing loss (SNHL), retinitis pigmentosa (RP), and vestibular dysfunction. There are currently nine confirmed and two suspected USH-causative genes, and a further three candidate loci have been mapped. The proteins encoded by these genes form complexes that play critical roles in the development and maintenance of cellular structures within the inner ear and retina, which have minimal capacity for repair or regeneration. In the cochlea, stereocilia are located on the apical surface of inner ear hair cells (HC) and are responsible for transducing mechanical stimuli from sound pressure waves into chemical signals. These signals are then detected by the auditory nerve fibers, transmitted to the brain and interpreted as sound. Disease-causing mutations in USH genes can destabilize the tip links that bind the stereocilia to each other, and cause defects in protein trafficking and stereocilia bundle morphology, thereby inhibiting mechanosensory transduction. This review summarizes the current knowledge on Usher syndrome with a particular emphasis on mutations in USH genes, USH protein structures, and functional analyses in animal models. Currently, there is no cure for USH. However, the genetic therapies that are rapidly developing will benefit from this compilation of detailed genetic information to identify the most effective strategies for restoring functional USH proteins.

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Defining Human Pluripotency

Cited by 65 publications

References 131 publications

The Chromatin Regulator ZMYM2 Restricts Human Pluripotent Stem Cell Growth and Is Essential for Teratoma Formation

The Chromatin Regulator ZMYM2 Restricts Human Pluripotent Stem Cell Growth and Is Essential for Teratoma Formation

Progress in Modeling and Targeting Inner Ear Disorders with Pluripotent Stem Cells

Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy

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