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1.
Cell ; 169(3): 483-496.e13, 2017 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-28413068

RESUMEN

Adult tissue stem cells (SCs) reside in niches, which, through intercellular contacts and signaling, influence SC behavior. Once activated, SCs typically give rise to short-lived transit-amplifying cells (TACs), which then progress to differentiate into their lineages. Here, using single-cell RNA-seq, we unearth unexpected heterogeneity among SCs and TACs of hair follicles. We trace the roots of this heterogeneity to micro-niches along epithelial-mesenchymal interfaces, where progenitors display molecular signatures reflective of spatially distinct local signals and intercellular interactions. Using lineage tracing, temporal single-cell analyses, and chromatin landscaping, we show that SC plasticity becomes restricted in a sequentially and spatially choreographed program, culminating in seven spatially arranged unilineage progenitors within TACs of mature follicles. By compartmentalizing SCs into micro-niches, tissues gain precise control over morphogenesis and regeneration: some progenitors specify lineages immediately, whereas others retain potency, preserving self-renewing features established early while progressively restricting lineages as they experience dynamic changes in microenvironment.


Asunto(s)
Células Madre Adultas/citología , Linaje de la Célula , Folículo Piloso/citología , Nicho de Células Madre , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Vía de Señalización Wnt
2.
Cell ; 169(4): 636-650.e14, 2017 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-28434617

RESUMEN

Tissue stem cells contribute to tissue regeneration and wound repair through cellular programs that can be hijacked by cancer cells. Here, we investigate such a phenomenon in skin, where during homeostasis, stem cells of the epidermis and hair follicle fuel their respective tissues. We find that breakdown of stem cell lineage confinement-granting privileges associated with both fates-is not only hallmark but also functional in cancer development. We show that lineage plasticity is critical in wound repair, where it operates transiently to redirect fates. Investigating mechanism, we discover that irrespective of cellular origin, lineage infidelity occurs in wounding when stress-responsive enhancers become activated and override homeostatic enhancers that govern lineage specificity. In cancer, stress-responsive transcription factor levels rise, causing lineage commanders to reach excess. When lineage and stress factors collaborate, they activate oncogenic enhancers that distinguish cancers from wounds.


Asunto(s)
Carcinoma de Células Escamosas/patología , Linaje de la Célula , Células Epidérmicas , Folículo Piloso/citología , Neoplasias Cutáneas/patología , Piel/citología , Células Madre/metabolismo , Animales , Línea Celular Tumoral , Cromatina/metabolismo , Epidermis/metabolismo , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias Cutáneas/metabolismo , Factores de Transcripción/metabolismo , Transcriptoma , Trasplante Heterólogo , Cicatrización de Heridas
3.
Proc Natl Acad Sci U S A ; 120(32): e2309967120, 2023 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-37523551

RESUMEN

Body fat distribution is a heritable risk factor for cardiovascular and metabolic disease. In humans, rare Inhibin beta E (INHBE, activin E) loss-of-function variants are associated with a lower waist-to-hip ratio and protection from type 2 diabetes. Hepatic fatty acid sensing promotes INHBE expression during fasting and in obese individuals, yet it is unclear how the hepatokine activin E governs body shape and energy metabolism. Here, we uncover activin E as a regulator of adipose energy storage. By suppressing ß-agonist-induced lipolysis, activin E promotes fat accumulation and adipocyte hypertrophy and contributes to adipose dysfunction in mice. Mechanistically, we demonstrate that activin E elicits its effect on adipose tissue through ACVR1C, activating SMAD2/3 signaling and suppressing PPARG target genes. Conversely, loss of activin E or ACVR1C in mice increases fat utilization, lowers adiposity, and drives PPARG-regulated gene signatures indicative of healthy adipose function. Our studies identify activin E-ACVR1C as a metabolic rheostat promoting liver-adipose cross talk to restrain excessive fat breakdown and preserve fat mass during prolonged fasting, a mechanism that is maladaptive in obese individuals.


Asunto(s)
Diabetes Mellitus Tipo 2 , Lipólisis , Humanos , Ratones , Animales , Activinas/metabolismo , Adiposidad/genética , Diabetes Mellitus Tipo 2/metabolismo , PPAR gamma/metabolismo , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Receptores de Activinas Tipo I/genética , Receptores de Activinas Tipo I/metabolismo
4.
Glycobiology ; 33(7): 591-604, 2023 08 14.
Artículo en Inglés | MEDLINE | ID: mdl-37341346

RESUMEN

V-set and immunoglobulin domain-containing 4 (VSIG4) is a complement receptor of the immunoglobulin superfamily that is specifically expressed on tissue resident macrophages, and its many reported functions and binding partners suggest a complex role in immune function. VSIG4 is reported to have a role in immune surveillance as well as in modulating diverse disease phenotypes such as infections, autoimmune conditions, and cancer. However, the mechanism(s) governing VSIG4's complex, context-dependent role in immune regulation remains elusive. Here, we identify cell surface and soluble glycosaminoglycans, specifically heparan sulfates, as novel binding partners of VSIG4. We demonstrate that genetic deletion of heparan sulfate synthesis enzymes or cleavage of cell-surface heparan sulfates reduced VSIG4 binding to the cell surface. Furthermore, binding studies demonstrate that VSIG4 interacts directly with heparan sulfates, with a preference for highly sulfated moieties and longer glycosaminoglycan chains. To assess the impact on VSIG4 biology, we show that heparan sulfates compete with known VSIG4 binding partners C3b and iC3b. Furthermore, mutagenesis studies indicate that this competition occurs through overlapping binding epitopes for heparan sulfates and complement on VSIG4. Together these data suggest a novel role for heparan sulfates in VSIG4-dependent immune modulation.


Asunto(s)
Glicosaminoglicanos , Heparitina Sulfato , Heparitina Sulfato/metabolismo , Glicosaminoglicanos/metabolismo , Receptores de Complemento/genética , Receptores de Complemento/metabolismo , Membrana Celular/metabolismo , Sulfatos
5.
Nature ; 521(7552): 366-70, 2015 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-25799994

RESUMEN

Adult stem cells occur in niches that balance self-renewal with lineage selection and progression during tissue homeostasis. Following injury, culture or transplantation, stem cells outside their niche often display fate flexibility. Here we show that super-enhancers underlie the identity, lineage commitment and plasticity of adult stem cells in vivo. Using hair follicle as a model, we map the global chromatin domains of hair follicle stem cells and their committed progenitors in their native microenvironments. We show that super-enhancers and their dense clusters ('epicentres') of transcription factor binding sites undergo remodelling upon lineage progression. New fate is acquired by decommissioning old and establishing new super-enhancers and/or epicentres, an auto-regulatory process that abates one master regulator subset while enhancing another. We further show that when outside their niche, either in vitro or in wound-repair, hair follicle stem cells dynamically remodel super-enhancers in response to changes in their microenvironment. Intriguingly, some key super-enhancers shift epicentres, enabling their genes to remain active and maintain a transitional state in an ever-changing transcriptional landscape. Finally, we identify SOX9 as a crucial chromatin rheostat of hair follicle stem cell super-enhancers, and provide functional evidence that super-enhancers are dynamic, dense transcription-factor-binding platforms which are acutely sensitive to pioneer master regulators whose levels define not only spatial and temporal features of lineage-status but also stemness, plasticity in transitional states and differentiation.


Asunto(s)
Adaptación Fisiológica , Células Madre Adultas/citología , Diferenciación Celular/genética , Linaje de la Célula/genética , Elementos de Facilitación Genéticos/genética , Folículo Piloso/citología , Factor de Transcripción SOX9/metabolismo , Células Madre Adultas/metabolismo , Animales , Secuencia de Bases , Cromatina/genética , Cromatina/metabolismo , Femenino , Ratones , Especificidad de Órganos , Nicho de Células Madre , Factores de Tiempo
6.
J Lipid Res ; 61(9): 1271-1286, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32646941

RESUMEN

Angiopoietin-like protein (ANGPTL)3 regulates plasma lipids by inhibiting LPL and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-C independently of the classical LDLR-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to LDLR mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic, and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3's novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR.


Asunto(s)
Proteínas Similares a la Angiopoyetina/metabolismo , LDL-Colesterol/sangre , VLDL-Colesterol/sangre , Proteína 3 Similar a la Angiopoyetina , Animales , Endotelio/metabolismo , Humanos , Ratones , Receptores de LDL/metabolismo
7.
Trends Genet ; 32(2): 89-100, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26689127

RESUMEN

Adult organisms rely on tissue stem cells for maintenance and repair. During homeostasis, the concerted action of local niche signals and epigenetic regulators establish stable gene expression patterns to ensure that stem cells are not lost over time. However, stem cells also provide host tissues with a remarkable plasticity to respond to perturbations. How adult stem cells choose and acquire new fates is unknown, but the genome-wide mapping of epigenetic landscapes suggests a critical role for chromatin remodeling in these processes. Here, we explore the emerging role of chromatin modifiers and pioneer transcription factors in adult stem cell fate decisions and plasticity, which ensure that selective lineage choices are only made when environmentally cued.


Asunto(s)
Cromatina/genética , Metilación de ADN , Células Madre/citología , Células Madre/fisiología , Factores de Transcripción/metabolismo , Células Madre Adultas , Linaje de la Célula , Cromatina/metabolismo , Epigénesis Genética , Silenciador del Gen , Humanos , Proteínas del Grupo Polycomb/genética , Proteínas del Grupo Polycomb/metabolismo , Factores de Transcripción/genética
8.
J Lipid Res ; 55(11): 2229-41, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25176985

RESUMEN

Fibroblast growth factor 21 (FGF21) is a PPARα-regulated gene elucidated in the liver of PPARα-deficient mice or PPARα agonist-treated mice. Mice globally lacking adipose triglyceride lipase (ATGL) exhibit a marked defect in TG catabolism associated with impaired PPARα-activated gene expression in the heart and liver, including a drastic reduction in hepatic FGF21 mRNA expression. Here we show that FGF21 mRNA expression is markedly increased in the heart of ATGL-deficient mice accompanied by elevated expression of endoplasmic reticulum (ER) stress markers, which can be reversed by reconstitution of ATGL expression in cardiac muscle. In line with this assumption, the induction of ER stress increases FGF21 mRNA expression in H9C2 cardiomyotubes. Cardiac FGF21 expression was also induced upon fasting of healthy mice, implicating a role of FGF21 in cardiac energy metabolism. To address this question, we generated and characterized mice with cardiac-specific overexpression of FGF21 (CM-Fgf21). FGF21 was efficiently secreted from cardiomyocytes of CM-Fgf21 mice, which moderately affected cardiac TG homeostasis, indicating a role for FGF21 in cardiac energy metabolism. Together, our results show that FGF21 expression is activated upon cardiac ER stress linked to defective lipolysis and that a persistent increase in circulating FGF21 levels interferes with cardiac and whole body energy homeostasis.


Asunto(s)
Estrés del Retículo Endoplásmico , Factores de Crecimiento de Fibroblastos/genética , Homeostasis , Miocardio/citología , Miocardio/metabolismo , Activación Transcripcional , Triglicéridos/metabolismo , Animales , Transporte Biológico , Línea Celular , Metabolismo Energético , Ayuno/metabolismo , Ácidos Grasos/metabolismo , Femenino , Glucosa/metabolismo , Lipasa/deficiencia , Masculino , Ratones , Ratones Transgénicos , Fibras Musculares Esqueléticas/metabolismo , Especificidad de Órganos , Oxidación-Reducción , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas
9.
Nat Cell Biol ; 25(8): 1185-1195, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37488435

RESUMEN

During development, progenitors simultaneously activate one lineage while silencing another, a feature highly regulated in adult stem cells but derailed in cancers. Equipped to bind cognate motifs in closed chromatin, pioneer factors operate at these crossroads, but how they perform fate switching remains elusive. Here we tackle this question with SOX9, a master regulator that diverts embryonic epidermal stem cells (EpdSCs) into becoming hair follicle stem cells. By engineering mice to re-activate SOX9 in adult EpdSCs, we trigger fate switching. Combining epigenetic, proteomic and functional analyses, we interrogate the ensuing chromatin and transcriptional dynamics, slowed temporally by the mature EpdSC niche microenvironment. We show that as SOX9 binds and opens key hair follicle enhancers de novo in EpdSCs, it simultaneously recruits co-factors away from epidermal enhancers, which are silenced. Unhinged from its normal regulation, sustained SOX9 subsequently activates oncogenic transcriptional regulators that chart the path to cancers typified by constitutive SOX9 expression.


Asunto(s)
Células Madre Adultas , Proteómica , Animales , Ratones , Células Madre Adultas/metabolismo , Diferenciación Celular , Cromatina/genética , Epigénesis Genética , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo
10.
Nat Cell Biol ; 22(6): 640-650, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32393888

RESUMEN

Tissue homeostasis and regeneration rely on resident stem cells (SCs), whose behaviour is regulated through niche-dependent crosstalk. The mechanisms underlying SC identity are still unfolding. Here, using spatiotemporal gene ablation in murine hair follicles, we uncover a critical role for the transcription factors (TFs) nuclear factor IB (NFIB) and IX (NFIX) in maintaining SC identity. Without NFI TFs, SCs lose their hair-regenerating capability, and produce skin bearing striking resemblance to irreversible human alopecia, which also displays reduced NFIs. Through single-cell transcriptomics, ATAC-Seq and ChIP-Seq profiling, we expose a key role for NFIB and NFIX in governing super-enhancer maintenance of the key hair follicle SC-specific TF genes. When NFIB and NFIX are genetically removed, the stemness epigenetic landscape is lost. Super-enhancers driving SC identity are decommissioned, while unwanted lineages are de-repressed ectopically. Together, our findings expose NFIB and NFIX as crucial rheostats of tissue homeostasis, functioning to safeguard the SC epigenome from a breach in lineage confinement that otherwise triggers irreversible tissue degeneration.


Asunto(s)
Alopecia/patología , Diferenciación Celular , Cromatina/metabolismo , Folículo Piloso/citología , Factores de Transcripción NFI/fisiología , Células Madre/citología , Alopecia/genética , Alopecia/metabolismo , Animales , Células Cultivadas , Cromatina/genética , Femenino , Folículo Piloso/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Regeneración , Células Madre/metabolismo
11.
Cell Stem Cell ; 22(3): 398-413.e7, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29337183

RESUMEN

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.


Asunto(s)
Linaje de la Célula , Ensamble y Desensamble de Cromatina , Folículo Piloso/citología , Transducción de Señal , Células Madre/citología , Células Madre/metabolismo , Acetilación , Animales , Secuencia de Bases , Proteínas Morfogenéticas Óseas/metabolismo , Cromatina/metabolismo , Elementos de Facilitación Genéticos/genética , Histonas/metabolismo , Lisina/metabolismo , Ratones Endogámicos C57BL , Fosforilación , Regeneración , Proteína Smad1/metabolismo , Factores de Tiempo , Factores de Transcripción/metabolismo , Vía de Señalización Wnt
12.
Elife ; 4: e10870, 2015 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-26590320

RESUMEN

Tumor-initiating stem cells (SCs) exhibit distinct patterns of transcription factors and gene expression compared to healthy counterparts. Here, we show that dramatic shifts in large open-chromatin domain (super-enhancer) landscapes underlie these differences and reflect tumor microenvironment. By in vivo super-enhancer and transcriptional profiling, we uncover a dynamic cancer-specific epigenetic network selectively enriched for binding motifs of a transcription factor cohort expressed in squamous cell carcinoma SCs (SCC-SCs). Many of their genes, including Ets2 and Elk3, are themselves regulated by SCC-SC super-enhancers suggesting a cooperative feed-forward loop. Malignant progression requires these genes, whose knockdown severely impairs tumor growth and prohibits progression from benign papillomas to SCCs. ETS2-deficiency disrupts the SCC-SC super-enhancer landscape and downstream cancer genes while ETS2-overactivation in epidermal-SCs induces hyperproliferation and SCC super-enhancer-associated genes Fos, Junb and Klf5. Together, our findings unearth an essential regulatory network required for the SCC-SC chromatin landscape and unveil its importance in malignant progression.


Asunto(s)
Carcinoma de Células Escamosas/patología , Cromatina/metabolismo , Redes Reguladoras de Genes , Proliferación Celular , Epigénesis Genética , Humanos
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