Archive | October 2015

Histone Demethylase Expression Enhances Human Somatic Cell Nuclear Transfer Efficiency and Promotes Derivation of Pluripotent Stem Cells

Bhaskar Chanda Stem Cell Zhang and colleagues show that, as they found previously in mouse, injection of a histone demethylase improves the efficiency of human SCNT reprogramming. Using this approach they were able to reduce variability in success from different egg donors and derive human NT-ESC lines from patients with age-related macular degeneration.

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Polycomb Complex PRC1 Preserves Intestinal Stem Cell Identity by Sustaining Wnt/β-Catenin Transcriptional Activity

Bhaskar Chanda Stem Cell Chiacchiera et al. show that PRC1 activity is essential to maintain integrity of the intestinal epithelium during homeostasis and in cancer. Mechanistically, PRC1 represses non-lineage-specific transcription factors that in turn directly affect β-catenin/Tcf transcriptional activity and Wnt-dependent intestinal stem cell self-renewal.

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Coordination of mA mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming

Bhaskar Chanda Stem Cell Aguillo et al. show that ZFP217 coordinates epigenetic and epitranscriptomic networks to control embryonic stem cell pluripotency and somatic cell reprogramming. ZFP217 directly activates core stem cell genes and restrains m6A deposition in their transcripts through interaction with METTL3, coupling transcription and mRNA methylation to control stemness.

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Rapid Conversion of Fibroblasts into Functional Forebrain GABAergic Interneurons by Direct Genetic Reprogramming

Bhaskar Chanda Stem Cell Colasante et al. identify a combination of five transcription factors that convert mouse and human fibroblasts into induced GABAergic telencephalic interneurons (iGABA-INs), which are functionally similar to bona fide GABAergic INs. Upon transplantation, iGABA-INs functionally integrate into host neuronal networks and inhibit excitatory neurons in the host hippocampus.

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Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation

Bhaskar Chanda Stem Cell Mazumdar et al. investigate the effects of leukemia-associated cohesin complex mutations on human hematopoietic stem and progenitor cells. Cohesin mutants are found to impair differentiation and enforce stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity, suggesting a mechanism contributing to leukemogenesis.

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Frequent Somatic Mutation in Adult Intestinal Stem Cells Drives Neoplasia and Genetic Mosaicism during Aging

Bhaskar Chanda Stem Cell Bardin and colleagues show that aging Drosophila intestinal stem cells (ISCs) acquire frequent spontaneous mutations, including frequent loss of heterozygosity arising from homologous mitotic recombination that results in clonal mosaicism. They also show spontaneous gene deletions and chromosomal rearrangements in aging ISCs, which can promote neoplasia formation through inactivating Notch.

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Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells

Bhaskar Chanda Stem Cell Through population analysis, Giani et al. show that rare mutations in SH2B3 associate with increased hemoglobin levels in humans. Applying this insight, they suppress SH2B3 in hematopoietic stem/progenitor cells and use CRISPR/Cas9 genome editing to inactivate it in embryonic stem cells to improve mature erythroid cell yield following differentiation.

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Regeneration of Thyroid Function by Transplantation of Differentiated Pluripotent Stem Cells

Bhaskar Chanda Stem Cell The molecular pathways governing thyroid differentiation are poorly understood. Kurmann et al. show that BMP4 and FGF2 activate key pathways that drive thyroid specification in vivo and in vitro, enabling differentiation of mouse and human pluripotent stem cells into thyroid follicular cells that produce thyroid hormones and rescue mouse hypothyroidism.

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Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons

Bhaskar Chanda Stem Cell In this study, Chen and colleagues demonstrate chemical reprogramming of human astrocytes into functional neurons with a cocktail of small molecules. This chemical reprogramming is mediated through epigenetic silencing of glial genes and transcriptional activation of neural transcription factors such as NeuroD1 and Neurogenin 2.

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Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects

Bhaskar Chanda Stem Cell Mertens and colleagues compare transcriptomes of human fibroblasts, induced neurons (iNs), iPSCs, iPSC-derived neurons, and brain samples from a broad range of aged donors, finding that iNs retain donor aging signatures, while iPSCs are rejuvenated. RanBP17 was consistently decreased during aging, leading to compromised nucleocytoplasmic compartmentalization in aged human cells.

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via Bhaskar Chanda UHN