Temporal Layering of Signaling Effectors Drives Chromatin Remodeling during Hair Follicle Stem Cell Lineage Progression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE100876 | GEO | 2018/01/11
SECONDARY ACCESSION(S): PRJNA393323
REPOSITORIES: GEO
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Project description:Tissue regeneration relies on resident stem cells (SCs), whose activity and lineage choices are influenced by the microenvironment. Exploiting the synchronized, cyclical bouts of tissue regeneration in hair follicles (HFs), we investigate how microenvironment dynamics shape the emergence of stem cell lineages. Employing epigenetic and ChIP-seq profiling, we uncover how signal-dependent transcription factors couple spatiotemporal cues to chromatin dynamics, thereby choreographing stem cell lineages. Using enhancer-driven reporters, mutagenesis, and genetics, we show that simultaneous BMP-inhibitory and WNT signals set the stage for lineage choices by establishing chromatin platforms permissive for diversification. Mechanistically, when binding of BMP effector pSMAD1 is relieved, enhancers driving HF-stem cell master regulators are silenced. Concomitantly, multipotent, lineage-fated enhancers silent in HF-stem cells become activated by exchanging WNT effectors TCF3/4 for LEF1. Throughout regeneration, lineage enhancers continue reliance upon LEF1 but then achieve specificity by accommodating additional incoming signaling effectors. Barriers to progenitor plasticity increase when diverse, signal-sensitive transcription factors shape LEF1-regulated enhancer dynamics.
| S-EPMC6425486 | biostudies-literature
Project description:Tissue regeneration relies on resident stem cells (SCs), whose activity and lineage choices are influenced by microenvironment. Exploiting the synchronized, cyclical bouts of tissue regeneration in hair follicles (HFs), we investigate how microenvironment dynamics shape the emergence of SC lineages. Employing epigenetic and ChIP-seq profiling, we uncover how signal-dependent transcription factors couple spatio-temporal cues to chromatin dynamics, thereby choreographing SC lineages. Using enhancer-driven reporters, mutagenesis and genetics, we show that simultaneous BMP-inhibitory and WNT signals set the stage for lineage choices by establishing chromatin platforms permissive for diversification. Mechanistically, when binding of BMP-effector pSMAD1 is relieved, super-enhancers driving HF-SC master regulators become silenced. Concomitantly, multipotent, lineage-fated super-enhancers silent in HF-SCs become activated by exchanging WNT-effectors TCF3/4 for LEF1. Throughout regeneration, lineage super-enhancers continue reliance upon LEF1, but then achieve specificity by accommodating additional incoming signaling effectors. Barriers to progenitor plasticity mount as diverse, signal-sensitive transcription factors shape LEF1-regulated super-enhancer dynamics.
2018-01-11 | GSE100874 | GEO
Project description:Tissue regeneration relies on resident stem cells (SCs), whose activity and lineage choices are influenced by microenvironment. Exploiting the synchronized, cyclical bouts of tissue regeneration in hair follicles (HFs), we investigate how microenvironment dynamics shape the emergence of SC lineages. Employing epigenetic and ChIP-seq profiling, we uncover how signal-dependent transcription factors couple spatio-temporal cues to chromatin dynamics, thereby choreographing SC lineages. Using enhancer-driven reporters, mutagenesis and genetics, we show that simultaneous BMP-inhibitory and WNT signals set the stage for lineage choices by establishing chromatin platforms permissive for diversification. Mechanistically, when binding of BMP-effector pSMAD1 is relieved, super-enhancers driving HF-SC master regulators become silenced. Concomitantly, multipotent, lineage-fated super-enhancers silent in HF-SCs become activated by exchanging WNT-effectors TCF3/4 for LEF1. Throughout regeneration, lineage super-enhancers continue reliance upon LEF1, but then achieve specificity by accommodating additional incoming signaling effectors. Barriers to progenitor plasticity mount as diverse, signal-sensitive transcription factors shape LEF1-regulated super-enhancer dynamics.
2018-01-11 | GSE100872 | GEO
Project description:Tissue regeneration relies on resident stem cells (SCs), whose activity and lineage choices are influenced by microenvironment. Exploiting the synchronized, cyclical bouts of tissue regeneration in hair follicles (HFs), we investigate how microenvironment dynamics shape the emergence of SC lineages. Employing epigenetic and ChIP-seq profiling, we uncover how signal-dependent transcription factors couple spatio-temporal cues to chromatin dynamics, thereby choreographing SC lineages. Using enhancer-driven reporters, mutagenesis and genetics, we show that simultaneous BMP-inhibitory and WNT signals set the stage for lineage choices by establishing chromatin platforms permissive for diversification. Mechanistically, when binding of BMP-effector pSMAD1 is relieved, super-enhancers driving HF-SC master regulators become silenced. Concomitantly, multipotent, lineage-fated super-enhancers silent in HF-SCs become activated by exchanging WNT-effectors TCF3/4 for LEF1. Throughout regeneration, lineage super-enhancers continue reliance upon LEF1, but then achieve specificity by accommodating additional incoming signaling effectors. Barriers to progenitor plasticity mount as diverse, signal-sensitive transcription factors shape LEF1-regulated super-enhancer dynamics.
2018-01-11 | GSE100875 | GEO
Project description:Temporal Layering of Signaling Effectors Drives Chromatin Remodeling during Hair Follicle Stem Cell Lineage Progression
| PRJNA393323 | ENA
Project description:Using mouse skin, where bountiful reservoirs of synchronized hair follicle stem cells (HF-SCs) fuel cycles of regeneration, we explore how adult SCs remodel chromatin in response to activating cues. By profiling global mRNA and chromatin changes in quiescent and activated HF-SCs and their committed, transit-amplifying (TA) progeny, we show that polycomb-group (PcG)-mediated H3K27-trimethylation features prominently in HF-lineage progression by mechanisms distinct from embryonic-SCs. In HF-SCs, PcG represses nonskin lineages and HF differentiation. In TA progeny, nonskin regulators remain PcG-repressed, HF-SC regulators acquire H3K27me3-marks, and HF-lineage regulators lose them. Interestingly, genes poised in embryonic stem cells, active in HF-SCs, and PcG-repressed in TA progeny encode not only key transcription factors, but also signaling regulators. We document their importance in balancing HF-SC quiescence, underscoring the power of chromatin mapping in dissecting SC behavior. Our findings explain how HF-SCs cycle through quiescent and activated states without losing stemness and define roles for PcG-mediated repression in governing a fate switch irreversibly.
| S-EPMC3166618 | biostudies-literature
Project description:Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated by a number of intrinsic and extrinsic mechanisms. Here we provide several lines of evidence to demonstrate that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis. Furthermore, lactate generation appears to be critical for the activation of HFSCs as deletion of lactate dehydrogenase (Ldha) prevented their activation. Conversely, genetically promoting lactate production in HFSCs through mitochondrial pyruvate carrier 1 (Mpc1) deletion accelerated their activation and the hair cycle. Finally, we identify small molecules that increase lactate production by stimulating Myc levels or inhibiting Mpc1 carrier activity and can topically induce the hair cycle. These data suggest that HFSCs maintain a metabolic state that allows them to remain dormant and yet quickly respond to appropriate proliferative stimuli.
| S-EPMC5657543 | biostudies-literature
Project description:Chromatin modification is pivotal to the epithelial-mesenchymal transition (EMT), which confers potent metastatic potential to cancer cells. Here, we report a role for the chromatin remodeling factor lymphoid-specific helicase (LSH) in nasopharyngeal carcinoma (NPC), a prevalent cancer in China. LSH expression was increased in NPC, where it was controlled by the Epstein-Barr virus-encoded protein LMP1. In NPC cells in vitro and in vivo, LSH promoted cancer progression in part by regulating expression of fumarate hydratase (FH), a core component of the tricarboxylic acid cycle. LSH bound to the FH promoter, recruiting the epigenetic silencer factor G9a to repress FH transcription. Clinically, we found that the concentration of TCA intermediates in NPC patient sera was deregulated in the presence of LSH. RNAi-mediated silencing of FH mimicked LSH overexpression, establishing FH as downstream mediator of LSH effects. The TCA intermediates ?-KG and citrate potentiated the malignant character of NPC cells, in part by altering IKK?-dependent EMT gene expression. In this manner, LSH furthered malignant progression of NPC by modifying cancer cell metabolism to support EMT. Cancer Res; 76(19); 5743-55. ©2016 AACR.
| S-EPMC7821962 | biostudies-literature
Project description:The hair-growth cycle, a complex biological system requiring coordinate alterations in gene expression and cellular behavior, provides a challenging model for investigating the interplay of specific transcriptional regulation events. Here we report that the Barx2 homeodomain factor serves as a regulator of hair follicle remodeling (catagen), and loss of Barx2 in mice causes a defect both in the initiation and progression of catagen, resulting in a protracted first catagen, and later, causing short hair in adult gene-deleted mice. Barx2 negatively regulates its own promoter, and our study highlights the role of Barx2 as a repressor in the skin that can, unexpectedly, functionally interact with two WD40-domain factors distantly related to the yeast corepressor Tup1. These two corepressors, transducin-like enhancer of split and transducin beta-like 1, function through distinct and independent interactions with Barx2 for the repression of gene targets, including the Barx2 gene itself, emphasizing the roles of complementary repression strategies in engrailed homology-1 motif-containing homeodomain factors. Together, our data suggest that the hair-remodeling defect of Barx2 mutant mice could be explained, in part, by failure to repress one or more critical target genes.
| S-EPMC553323 | biostudies-literature
Project description:Observations in thyroid patients and experimental animals show that the skin is an important target for the thyroid hormones. We previously showed that deletion in mice of the thyroid hormone nuclear receptors TR?1 and TR? (the main thyroid hormone-binding isoforms) results in impaired epidermal proliferation, hair growth, and wound healing. Stem cells located at the bulges of the hair follicles are responsible for hair cycling and contribute to the regeneration of the new epidermis after wounding. Therefore a reduction in the number or function of the bulge stem cells could be responsible for this phenotype. Bulge cells show increased levels of epigenetic repressive marks, can retain bromodeoxyuridine labeling for a long time, and have colony-forming efficiency (CFE) in vitro. Here we demonstrate that mice lacking TRs do not have a decrease of the bulge stem cell population. Instead, they show an increase of label-retaining cells (LRCs) in the bulges and enhanced CFE in vitro. Reduced activation of stem cells leading to their accumulation in the bulges is indicated by a strongly reduced response to mobilization by 12-O-tetradecanolyphorbol-13-acetate. Altered function of the bulge stem cells is associated with aberrant activation of Smad signaling, leading to reduced nuclear accumulation of ?-catenin, which is crucial for stem cell proliferation and mobilization. LRCs of TR-deficient mice also show increased levels of epigenetic repressive marks. We conclude that thyroid hormone signaling is an important determinant of the mobilization of stem cells out of their niche in the hair bulge. These findings correlate with skin defects observed in mice and alterations found in human thyroid disorders.
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