Rapid remodeling of poised chromatin landscapes and transcription factor repurposing facilitate gene induction in natural killer cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE145299 | GEO | 2020/10/28
REPOSITORIES: GEO
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Project description:Rapid remodeling of poised chromatin landscapes and transcription factor repurposing facilitate gene induction in natural killer cells
| PRJNA606695 | ENA
Project description:The reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) upon overexpression of OCT4, KLF4, SOX2 and c-MYC (OKSM) provides a powerful system to interrogate basic mechanisms of cell fate change. However, iPSC formation with standard methods is typically protracted and inefficient, resulting in heterogeneous cell populations. We show that exposure of OKSM-expressing cells to both ascorbic acid and a GSK3-β inhibitor (AGi) facilitates more synchronous and rapid iPSC formation from several mouse cell types. AGi treatment restored the ability of refractory cell populations to yield iPSC colonies, and it attenuated the activation of developmental regulators commonly observed during the reprogramming process. Moreover, AGi supplementation gave rise to chimera-competent iPSCs after as little as 48 h of OKSM expression. Our results offer a simple modification to the reprogramming protocol, facilitating iPSC induction at unparalleled efficiencies and enabling dissection of the underlying mechanisms in more homogeneous cell populations. 18 samples were analyzed in total, samples represent bulk cultures of reprogrammable-MEFs (Rep-MEFs) that express OKSM and were supplemented with ascorbic acid and GSK3i during iPS cell induction. Control samples represent similar bulk cultures of reprogrammable-MEFs that express OKSM but were not supplemented with ascorbic acid and GSK3i during iPS cell induction. GMP-iPSCs were generated using 48 hours of OKSM+AGi induction. Fibroblast-iPSCs were generated using 96 hours of OKSM+AGi induction.
2014-09-23 | E-GEOD-57774 | biostudies-arrayexpress
Project description:The reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) upon overexpression of OCT4, KLF4, SOX2 and c-MYC (OKSM) provides a powerful system to interrogate basic mechanisms of cell fate change. However, iPSC formation with standard methods is typically protracted and inefficient, resulting in heterogeneous cell populations. We show that exposure of OKSM-expressing cells to both ascorbic acid and a GSK3-β inhibitor (AGi) facilitates more synchronous and rapid iPSC formation from several mouse cell types. AGi treatment restored the ability of refractory cell populations to yield iPSC colonies, and it attenuated the activation of developmental regulators commonly observed during the reprogramming process. Moreover, AGi supplementation gave rise to chimera-competent iPSCs after as little as 48 h of OKSM expression. Our results offer a simple modification to the reprogramming protocol, facilitating iPSC induction at unparalleled efficiencies and enabling dissection of the underlying mechanisms in more homogeneous cell populations.
2014-09-23 | GSE57774 | GEO
Project description:BackgroundThe male germline transcriptome changes dramatically during the mitosis-to-meiosis transition to activate late spermatogenesis genes and to transiently suppress genes commonly expressed in somatic lineages and spermatogenesis progenitor cells, termed somatic/progenitor genes.ResultsThese changes reflect epigenetic regulation. Induction of late spermatogenesis genes during spermatogenesis is facilitated by poised chromatin established in the stem cell phases of spermatogonia, whereas silencing of somatic/progenitor genes during meiosis and postmeiosis is associated with formation of bivalent domains which also allows the recovery of the somatic/progenitor program after fertilization. Importantly, during spermatogenesis mechanisms of epigenetic regulation on sex chromosomes are different from autosomes: X-linked somatic/progenitor genes are suppressed by meiotic sex chromosome inactivation without deposition of H3K27me3.ConclusionsOur results suggest that bivalent H3K27me3 and H3K4me2/3 domains are not limited to developmental promoters (which maintain bivalent domains that are silent throughout the reproductive cycle), but also underlie reversible silencing of somatic/progenitor genes during the mitosis-to-meiosis transition in late spermatogenesis.
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Project description:In the COVID-19 pandemic, drug repositioning has presented itself as an alternative to the time-consuming process of generating new drugs. This review describes a drug repurposing process that is based on a new data-driven approach: we put forward five information paths that associate COVID-19-related genes and COVID-19 symptoms with drugs that directly target these gene products, that target the symptoms or that treat diseases that are symptomatically or genetically similar to COVID-19. The intersection of the five information paths results in a list of 13 drugs that we suggest as potential candidates against COVID-19. In addition, we have found information in published studies and in clinical trials that support the therapeutic potential of the drugs in our final list.
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Project description:Group 3 innate lymphoid cells (ILC3s) are crucial for the maintenance of host-microbiota homeostasis in gastrointestinal mucosal tissues. The mechanisms that maintain lineage identity of intestinal ILC3s, and ILC3s-mediated orchestration of microbiota and mucosal T cell immunity are elusive. Here, we identified BATF as a gatekeeper of ILC3s homeostasis in the gut. Depletion of BATF in ILC3s resulted in excessive interferon-γ production, dysbiosis, aberrant T cell immune responses and spontaneous inflammatory bowel disease (IBD), which was considerably ameliorated by removal of adaptive immunity or antibiotic treatment. Mechanistically, BATF directly regulates ILC3s identity by globally shapes chromatin landscape of ILC3s. BATF directly binds to the cis-regulatory elements of type 1 effector genes, restrains their chromatin accessibility and inhibits their expression. Conversely, BATF promotes chromatin accessibility of genes involved in MHCII antigen processing and presentation pathways. Collectively, our findings reveal BATF is a promising candidate to maintain ILC3s stability and coordinate ILC3s–mediated control of intestinal homeostasis.
2022-08-31 | GSE168078 | GEO
Project description:Murine neonates typically mount Th2-biased immune responses. This entails a cell-intrinsic component whose molecular basis is unknown. We found that neonatal CD4(+) T cells are uniquely poised for rapid Th2 function. Within 24 h of activation, neonatal CD4(+) cells made high levels of IL-4 and IL-13 mRNA and protein. The rapid high-level IL-4 production arose from a small subpopulation of cells, did not require cell cycle entry, and was unaffected by pharmacologic DNA demethylation. CpG methylation analyses in resting neonatal cells revealed pre-existing hypomethylation at a key Th2 cytokine regulatory region, termed conserved noncoding sequence 1 (CNS-1). Robust Th2 function and increased CNS-1 demethylation was a stable property that persisted in neonatal Th2 effectors. The transcription factor STAT6 was not required for CNS-1 demethylation and this state was already established in neonatal CD4 single-positive thymocytes. CNS-1 demethylation levels were much greater in IL-4-expressing CD4 single-positive thymocytes compared with unactivated cells. Together, these results indicate that neonatal CD4+ T cells possess distinct qualities that could predispose them toward rapid, effector-like Th2 function.
| S-EPMC2112939 | biostudies-literature
Project description:Group 3 innate lymphoid cells (ILC3s) are crucial for the maintenance of host-microbiota homeostasis in gastrointestinal mucosal tissues. The mechanisms that maintain lineage identity of intestinal ILC3s, and ILC3s-mediated orchestration of microbiota and mucosal T cell immunity are elusive. Here, we identified BATF as a gatekeeper of ILC3s homeostasis in the gut. Depletion of BATF in ILC3s resulted in excessive interferon-γ production, dysbiosis, aberrant T cell immune responses and spontaneous inflammatory bowel disease (IBD), which was considerably ameliorated by removal of adaptive immunity or antibiotic treatment. Mechanistically, BATF directly regulates ILC3s identity by globally shapes chromatin landscape of ILC3s. BATF directly binds to the cis-regulatory elements of type 1 effector genes, restrains their chromatin accessibility and inhibits their expression. Conversely, BATF promotes chromatin accessibility of genes involved in MHCII antigen processing and presentation pathways. Collectively, our findings reveal BATF is a promising candidate to maintain ILC3s stability and coordinate ILC3s–mediated control of intestinal homeostasis.
2022-09-08 | GSE212590 | GEO
Project description:How transcription factors (TFs) reprogram one cell lineage to another remains unclear. Here, we define chromatin accessibility changes induced by the proneural TF Ascl1 throughout conversion of fibroblasts into induced neuronal (iN) cells. Thousands of genomic loci are affected as early as 12 hours after Ascl1 induction. Surprisingly, over 80% of the accessibility changes occur between days 2 and 5 of the 3-week reprogramming process. This chromatin switch coincides with robust activation of endogenous neuronal TFs and nucleosome phasing of neuronal promoters and enhancers. Subsequent morphological and functional maturation of iN cells are accomplished with relatively little chromatin reconfiguration. Integrating chromatin accessibility and transcriptome changes, we built a network model of dynamic TF regulation during iN cell reprogramming, and identified Zfp238, Sox8 and Dlx3 as key TFs downstream of Ascl1. These results reveal a singular, coordinated epigenomic switch during direct reprogramming, in contrast to step-wise cell fate transitions in development.
2017-09-25 | GSE101397 | GEO
Project description:Evolution is an adaptive walk through a hypothetical fitness landscape, which depicts the relationship between genotypes and the fitness of each corresponding phenotype. We constructed an empirical fitness landscape for a catalytic RNA by combining next-generation sequencing, computational analysis, and "serial depletion," an in vitro selection protocol. By determining the reaction rate constant for every point mutant of a catalytic RNA, we demonstrated that abundance in serially depleted pools correlates with biochemical activity (correlation coefficient r = 0.67, standard score Z = 7.4). Therefore, enumeration of each genotype by deep sequencing yielded a fitness landscape containing ~10(7) unique sequences, without requiring measurement of the phenotypic fitness for each sequence. High-throughput mapping between genotype and phenotype may apply to artificial selections, host-pathogen interactions, and other biomedically relevant evolutionary phenomena.
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