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1.
Cell ; 155(1): 135-47, 2013 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-24074866

RESUMEN

Self-renewal and differentiation of stem cells are fundamentally associated with cell-cycle progression to enable tissue specification, organ homeostasis, and potentially tumorigenesis. However, technical challenges have impaired the study of the molecular interactions coordinating cell fate choice and cell-cycle progression. Here, we bypass these limitations by using the FUCCI reporter system in human pluripotent stem cells and show that their capacity of differentiation varies during the progression of their cell cycle. These mechanisms are governed by the cell-cycle regulators cyclin D1-3 that control differentiation signals such as the TGF-ß-Smad2/3 pathway. Conversely, cell-cycle manipulation using a small molecule directs differentiation of hPSCs and provides an approach to generate cell types with a clinical interest. Our results demonstrate that cell fate decisions are tightly associated with the cell-cycle machinery and reveal insights in the mechanisms synchronizing differentiation and proliferation in developing tissues.


Asunto(s)
Ciclo Celular , Diferenciación Celular , Ciclina D/metabolismo , Células Madre Embrionarias/citología , Transducción de Señal , Ciclina D/genética , Células Madre Embrionarias/metabolismo , Fase G1 , Técnicas de Silenciamiento del Gen , Humanos , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Proteína Smad2/genética , Proteína smad3/genética
2.
Gastroenterology ; 166(1): 139-154, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37739089

RESUMEN

BACKGROUND & AIMS: The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood, which hampers the development of novel strategies for eliminating CSCs. METHODS: By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodeling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFß/Activin-SMAD2/3 signaling pathway. RESULTS: Inhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumors from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. CONCLUSIONS: Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animales , Humanos , Ratones , Proteínas que Contienen Bromodominio , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Transformación Celular Neoplásica/patología , Gemcitabina , Células Madre Neoplásicas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteína Smad2/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
3.
Cell ; 156(6): 1338, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-28898638
4.
Genes Dev ; 30(4): 421-33, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26883361

RESUMEN

Coordination of differentiation and cell cycle progression represents an essential process for embryonic development and adult tissue homeostasis. These mechanisms ultimately determine the quantities of specific cell types that are generated. Despite their importance, the precise molecular interplays between cell cycle machinery and master regulators of cell fate choice remain to be fully uncovered. Here, we demonstrate that cell cycle regulators Cyclin D1-3 control cell fate decisions in human pluripotent stem cells by recruiting transcriptional corepressors and coactivator complexes onto neuroectoderm, mesoderm, and endoderm genes. This activity results in blocking the core transcriptional network necessary for endoderm specification while promoting neuroectoderm factors. The genomic location of Cyclin Ds is determined by their interactions with the transcription factors SP1 and E2Fs, which result in the assembly of cell cycle-controlled transcriptional complexes. These results reveal how the cell cycle orchestrates transcriptional networks and epigenetic modifiers to instruct cell fate decisions.


Asunto(s)
Ciclo Celular/genética , Diferenciación Celular/genética , Ciclina D/genética , Ciclina D/metabolismo , Células Madre Embrionarias/citología , Regulación del Desarrollo de la Expresión Génica , Cromatina/metabolismo , Endodermo/citología , Epigénesis Genética , Estudio de Asociación del Genoma Completo , Placa Neural/citología , Fosforilación , Unión Proteica
5.
Semin Cancer Biol ; 87: 48-83, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36347438

RESUMEN

Cell identity is largely determined by its transcriptional profile. In tumour, deregulation of transcription factor expression and/or activity enables cancer cell to acquire a stem-like state characterised by capacity to self-renew, differentiate and form tumours in vivo. These stem-like cancer cells are highly metastatic and therapy resistant, thus warranting a more complete understanding of the molecular mechanisms downstream of the transcription factors that mediate the establishment of stemness state. Here, we review recent research findings that provide a mechanistic link between the commonly deregulated transcription factors and stemness in cancer. In particular, we describe the role of master transcription factors (SOX, OCT4, NANOG, KLF, BRACHYURY, SALL, HOX, FOX and RUNX), signalling-regulated transcription factors (SMAD, ß-catenin, YAP, TAZ, AP-1, NOTCH, STAT, GLI, ETS and NF-κB) and unclassified transcription factors (c-MYC, HIF, EMT transcription factors and P53) across diverse tumour types, thereby yielding a comprehensive overview identifying shared downstream targets, highlighting unique mechanisms and discussing complexities.


Asunto(s)
Neoplasias , Factores de Transcripción , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células Madre Neoplásicas/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Línea Celular Tumoral
6.
Circulation ; 145(22): 1663-1683, 2022 05 31.
Artículo en Inglés | MEDLINE | ID: mdl-35400201

RESUMEN

BACKGROUND: Transcriptional reconfiguration is central to heart failure, the most common cause of which is dilated cardiomyopathy (DCM). The effect of 3-dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human DCM remains elusive. METHODS: We generated a compendium of 3-dimensional epigenome and transcriptome maps from 101 biobanked human DCM and nonfailing heart tissues through highly integrative chromatin immunoprecipitation (H3K27ac [acetylation of lysine 27 on histone H3]), in situ high-throughput chromosome conformation capture, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin using sequencing, and RNA sequencing. We used human induced pluripotent stem cell-derived cardiomyocytes and mouse models to interrogate the key transcription factor implicated in 3-dimensional chromatin organization and transcriptional regulation in DCM pathogenesis. RESULTS: We discovered that the active regulatory elements (H3K27ac peaks) and their connectome (H3K27ac loops) were extensively reprogrammed in DCM hearts and contributed to transcriptional dysregulation implicated in DCM development. For example, we identified that nontranscribing NPPA-AS1 (natriuretic peptide A antisense RNA 1) promoter functions as an enhancer and physically interacts with the NPPA (natriuretic peptide A) and NPPB (natriuretic peptide B) promoters, leading to the cotranscription of NPPA and NPPB in DCM hearts. We revealed that DCM-enriched H3K27ac loops largely resided in conserved high-order chromatin architectures (compartments, topologically associating domains) and their anchors unexpectedly had equivalent chromatin accessibility. We discovered that the DCM-enriched H3K27ac loop anchors exhibited a strong enrichment for HAND1 (heart and neural crest derivatives expressed 1), a key transcription factor involved in early cardiogenesis. In line with this, its protein expression was upregulated in human DCM and mouse failing hearts. To further validate whether HAND1 is a causal driver for the reprogramming of enhancer-promoter connectome in DCM hearts, we performed comprehensive 3-dimensional epigenome mappings in human induced pluripotent stem cell-derived cardiomyocytes. We found that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced a distinct gain of enhancer-promoter connectivity and correspondingly increased the expression of their connected genes implicated in DCM pathogenesis, thus recapitulating the transcriptional signature in human DCM hearts. Electrophysiology analysis demonstrated that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of Hand1 in the mouse hearts resulted in dilated cardiac remodeling with impaired contractility/Ca2+ handling in cardiomyocytes, increased ratio of heart weight/body weight, and compromised cardiac function, which were ascribed to recapitulation of transcriptional reprogramming in DCM. CONCLUSIONS: This study provided novel chromatin topology insights into DCM pathogenesis and illustrated a model whereby a single transcription factor (HAND1) reprograms the genome-wide enhancer-promoter connectome to drive DCM pathogenesis.


Asunto(s)
Cardiomiopatía Dilatada , Células Madre Pluripotentes Inducidas , Animales , Cardiomiopatía Dilatada/metabolismo , Cromatina/genética , Cromatina/metabolismo , Histonas/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Factores de Transcripción/genética
7.
Trends Genet ; 36(9): 634-637, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32561118

RESUMEN

Ramanand et al. perform the first high-resolution 3D genome mapping via ChIA-PET to capture RNAPII-associated chromatin interactions in normal prostate epithelial and prostate cancer cells. They describe how genetics, epigenetics, and the 3D genome architecture are coordinated in the aberrant gene expression that drives prostate cancer development.


Asunto(s)
Cromatina , Neoplasias , Mapeo Cromosómico , Cromosomas , Genoma , Masculino , ARN Polimerasa II
8.
Genes Dev ; 29(7): 702-17, 2015 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-25805847

RESUMEN

Stem cells can self-renew and differentiate into multiple cell types. These characteristics are maintained by the combination of specific signaling pathways and transcription factors that cooperate to establish a unique epigenetic state. Despite the broad interest of these mechanisms, the precise molecular controls by which extracellular signals organize epigenetic marks to confer multipotency remain to be uncovered. Here, we use human embryonic stem cells (hESCs) to show that the Activin-SMAD2/3 signaling pathway cooperates with the core pluripotency factor NANOG to recruit the DPY30-COMPASS histone modifiers onto key developmental genes. Functional studies demonstrate the importance of these interactions for correct histone 3 Lys4 trimethylation and also self-renewal and differentiation. Finally, genetic studies in mice show that Dpy30 is also necessary to maintain pluripotency in the pregastrulation embryo, thereby confirming the existence of similar regulations in vivo during early embryonic development. Our results reveal the mechanisms by which extracellular factors coordinate chromatin status and cell fate decisions in hESCs.


Asunto(s)
Activinas/metabolismo , Diferenciación Celular/genética , Cromatina/genética , Histonas/genética , Proteínas de Homeodominio/metabolismo , Proteína Nodal/metabolismo , Transducción de Señal , Animales , Células Cultivadas , Cromatina/metabolismo , Embrión de Mamíferos , Células Madre Embrionarias , Epigénesis Genética/genética , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Ratones , Proteína Homeótica Nanog , Proteína Smad2/metabolismo , Proteína smad3/metabolismo
9.
Mol Ther ; 29(3): 920-936, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33429081

RESUMEN

Pancreatic cancer remains a grueling disease that is projected to become the second-deadliest cancer in the next decade. Standard treatment of pancreatic cancer is chemotherapy, which mainly targets the differentiated population of tumor cells; however, it paradoxically sets the roots of tumor relapse by the selective enrichment of intrinsically chemoresistant pancreatic cancer stem cells that are equipped with an indefinite capacity for self-renewal and differentiation, resulting in tumor regeneration and an overall anemic response to chemotherapy. Crosstalk between pancreatic tumor cells and the surrounding stromal microenvironment is also involved in the development of chemoresistance by creating a supportive niche, which enhances the stemness features and tumorigenicity of pancreatic cancer cells. In addition, the desmoplastic nature of the tumor-associated stroma acts as a physical barrier, which limits the intratumoral delivery of chemotherapeutics. In this review, we mainly focus on the transforming growth factor beta 1 (TGFB1)/inhibin subunit beta A (INHBA) homodimer/Nodal-SMAD2/3 signaling network in pancreatic cancer as a pivotal central node that regulates multiple key mechanisms involved in the development of chemoresistance, including enhancement of the stem cell-like properties and tumorigenicity of pancreatic cancer cells, mediating cooperative interactions between pancreatic cancer cells and the surrounding stroma, as well as regulating the deposition of extracellular matrix proteins within the tumor microenvironment.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Terapia Molecular Dirigida , Neoplasias Pancreáticas/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Humanos , Subunidades beta de Inhibinas/antagonistas & inhibidores , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Proteína Nodal/antagonistas & inhibidores , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Transducción de Señal , Proteína Smad2/antagonistas & inhibidores , Proteína smad3/antagonistas & inhibidores , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Microambiente Tumoral
10.
Nucleic Acids Res ; 48(19): 10632-10647, 2020 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-32941624

RESUMEN

Cancer development and progression are demarcated by transcriptional dysregulation, which is largely attributed to aberrant chromatin architecture. Recent transformative technologies have enabled researchers to examine the genome organization at an unprecedented dimension and precision. In particular, increasing evidence supports the essential roles of 3D chromatin architecture in transcriptional homeostasis and proposes its alterations as prominent causes of human cancer. In this article, we will discuss the recent findings on enhancers, enhancer-promoter interaction, chromatin topology, phase separation and explore their potential mechanisms in shaping transcriptional dysregulation in cancer progression. In addition, we will propose our views on how to employ state-of-the-art technologies to decode the unanswered questions in this field. Overall, this article motivates the study of 3D chromatin architecture in cancer, which allows for a better understanding of its pathogenesis and develop novel approaches for diagnosis and treatment of cancer.


Asunto(s)
Ensamble y Desensamble de Cromatina , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Animales , Epigénesis Genética , Humanos
11.
Int J Cancer ; 148(12): 2884-2897, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-33197277

RESUMEN

Cancerous tumours contain a rare subset of cells with stem-like properties that are termed cancer stem cells (CSCs). CSCs are defined by their ability to divide both symmetrically and asymmetrically, to initiate new tumour growth and to tolerate the foreign niches required for metastatic dissemination. Accumulating evidence suggests that tumours arise from cells with stem-like properties, the generation of CSCs is therefore likely to be an initiatory event in carcinogenesis. Furthermore, CSCs in established tumours exist in a dynamic and plastic state, with nonstem tumour cells thought to be capable of de-differentiation to CSCs. The regulation of the CSC state both during tumour initiation and within established tumours is a desirable therapeutic target and is mediated by epigenetic factors. In this review, we will explore the epigenetic parallels between induced pluripotency and the generation of CSCs, and discuss how the epigenetic regulation of CSCs opens up novel opportunities for therapeutic intervention.


Asunto(s)
Epigénesis Genética , Neoplasias/genética , Células Madre Neoplásicas/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Metilación de ADN , Epigénesis Genética/efectos de los fármacos , Histonas/metabolismo , Humanos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Células Madre Neoplásicas/efectos de los fármacos
12.
Basic Res Cardiol ; 116(1): 49, 2021 08 14.
Artículo en Inglés | MEDLINE | ID: mdl-34392401

RESUMEN

Metabolic function and energy production in eukaryotic cells are regulated by mitochondria, which have been recognized as the intracellular 'powerhouses' of eukaryotic cells for their regulation of cellular homeostasis. Mitochondrial function is important not only in normal developmental and physiological processes, but also in a variety of human pathologies, including cardiac diseases. An emerging topic in the field of cardiovascular medicine is the implication of mitochondrial nucleoid for metabolic reprogramming. This review describes the linear/3D architecture of the mitochondrial nucleoid (e.g., highly organized protein-DNA structure of nucleoid) and how it is regulated by a variety of factors, such as noncoding RNA and its associated R-loop, for metabolic reprogramming in cardiac diseases. In addition, we highlight many of the presently unsolved questions regarding cardiac metabolism in terms of bidirectional signaling of mitochondrial nucleoid and 3D chromatin structure in the nucleus. In particular, we explore novel techniques to dissect the 3D structure of mitochondrial nucleoid and propose new insights into the mitochondrial retrograde signaling, and how it regulates the nuclear (3D) chromatin structures in mitochondrial diseases.


Asunto(s)
Cardiopatías , Mitocondrias , Núcleo Celular , Homeostasis , Humanos , Transducción de Señal
13.
Development ; 142(4): 607-19, 2015 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-25670788

RESUMEN

Activin/Nodal growth factors control a broad range of biological processes, including early cell fate decisions, organogenesis and adult tissue homeostasis. Here, we provide an overview of the mechanisms by which the Activin/Nodal signalling pathway governs stem cell function in these different stages of development. We describe recent findings that associate Activin/Nodal signalling to pathological conditions, focusing on cancer stem cells in tumorigenesis and its potential as a target for therapies. Moreover, we will discuss future directions and questions that currently remain unanswered on the role of Activin/Nodal signalling in stem cell self-renewal, differentiation and proliferation.


Asunto(s)
Activinas/metabolismo , Proteína Nodal/metabolismo , Activinas/genética , Animales , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Humanos , Proteína Nodal/genética , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiología , Células Madre/citología , Células Madre/metabolismo
16.
Protein Cell ; 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38758030

RESUMEN

Tissue formation and organ homeostasis is achieved by precise coordination of proliferation and differentiation of stem cells and progenitors. While deregulation of these processes can result in degenerative disease or cancer, their molecular interplays remain unclear. Here we show that the switch of human pluripotent stem cell (hPSC) self-renewal to differentiation is associated with the induction of distinct cyclin dependent kinase inhibitors (CDKIs). In hPSCs, Activin/Nodal/TGFß signalling maintains CDKIs in a poised state via SMAD2/3-NANOG-OCT4-EZH2-SNON transcriptional complex. Upon gradual differentiation, CDKIs are induced by successive transcriptional complexes between SMAD2/3-SMYD2 and developmental regulators such as EOMES, thereby lengthening the G1 phase. This, in turn, induces SMAD2/3 transcriptional activity by blocking its linker phosphorylation. Such SMAD2/3-CDKI positive feedback loops drive the exit from pluripotency and stepwise cell fate specification that could be harnessed for producing cells for therapeutic applications. Our study uncovers fundamental mechanisms how cell fate specification is interconnected to cell cycle dynamics and provides insight to autonomous circuitries governing tissue self-formation.

17.
Nat Commun ; 15(1): 3580, 2024 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-38678032

RESUMEN

The lethality, chemoresistance and metastatic characteristics of cancers are associated with phenotypically plastic cancer stem cells (CSCs). How the non-cell autonomous signalling pathways and cell-autonomous transcriptional machinery orchestrate the stem cell-like characteristics of CSCs is still poorly understood. Here we use a quantitative proteomic approach for identifying secreted proteins of CSCs in pancreatic cancer. We uncover that the cell-autonomous E2F1/4-pRb/RBL2 axis balances non-cell-autonomous signalling in healthy ductal cells but becomes deregulated upon KRAS mutation. E2F1 and E2F4 induce whereas pRb/RBL2 reduce WNT ligand expression (e.g. WNT7A, WNT7B, WNT10A, WNT4) thereby regulating self-renewal, chemoresistance and invasiveness of CSCs in both PDAC and breast cancer, and fibroblast proliferation. Screening for epigenetic enzymes identifies GCN5 as a regulator of CSCs that deposits H3K9ac onto WNT promoters and enhancers. Collectively, paracrine signalling pathways are controlled by the E2F-GCN5-RB axis in diverse cancers and this could be a therapeutic target for eliminating CSCs.


Asunto(s)
Factor de Transcripción E2F1 , Factor de Transcripción E2F4 , Células Madre Neoplásicas , Neoplasias Pancreáticas , Comunicación Paracrina , Humanos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Factor de Transcripción E2F1/metabolismo , Factor de Transcripción E2F1/genética , Línea Celular Tumoral , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Factor de Transcripción E2F4/metabolismo , Factor de Transcripción E2F4/genética , Animales , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proteínas Wnt/metabolismo , Proteínas Wnt/genética , Proteína de Retinoblastoma/metabolismo , Proteína de Retinoblastoma/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Factores de Transcripción p300-CBP/metabolismo , Factores de Transcripción p300-CBP/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Femenino , Proliferación Celular , Ratones , Transducción de Señal , Resistencia a Antineoplásicos/genética
18.
Trends Pharmacol Sci ; 44(5): 255-257, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36934024

RESUMEN

The clinical efficacy and durability of KRASG12C-targeted therapies are limited by the development of resistance mechanisms. Here, we provide a review of recent KRASG12C-targeted therapy and immunotherapy-unifying strategies that utilize covalently modified peptide/MHC class I complexes as tumor-specific neoantigens to tag drug-resistant cancer cells for destruction with hapten-based immunotherapeutics.


Asunto(s)
Neoplasias , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Mutación , Neoplasias/terapia , Resultado del Tratamiento , Inmunoterapia
19.
Cell Rep ; 42(9): 113146, 2023 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-37725511

RESUMEN

The retinoblastoma family proteins (RBs) and E2F transcription factors are cell-autonomous regulators of cell-cycle progression, but they also impact fate choice in addition to tumor suppression. The range of mechanisms involved remains to be uncovered. Here, we show that RBs, particularly RBL2/p130, repress WNT ligands such as WNT4 and WNT8A, thereby directing ectoderm specification between neural crest to neuroepithelium. RBL2 achieves this function through cell-cycle-dependent cooperation with E2Fs and GCN5 on the regulatory regions of WNT loci, which direct neuroepithelial versus neural crest specification by temporal fluctuations of WNT/ß-catenin and DLL/NOTCH signaling activity. Thus, the RB-E2F bona fide cell-autonomous axis controls cell fate decisions, and RBL2 regulates field effects via WNT ligands. This reveals a non-cell-autonomous function of RBL2-E2F in stem cell and tissue progenitor differentiation that has broader implications for cell-cycle-dependent cell fate specification in organogenesis, adult stem cells, tissue homeostasis, and tumorigenesis.


Asunto(s)
Tipificación del Cuerpo , Proteína de Retinoblastoma , Transducción de Señal , Humanos , Ciclo Celular , Diferenciación Celular , División Celular , Factores de Transcripción E2F/genética , Factores de Transcripción E2F/metabolismo , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo
20.
Nat Commun ; 14(1): 405, 2023 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-36697417

RESUMEN

Stem cells undergo cellular division during their differentiation to produce daughter cells with a new cellular identity. However, the epigenetic events and molecular mechanisms occurring between consecutive cell divisions have been insufficiently studied due to technical limitations. Here, using the FUCCI reporter we developed a cell-cycle synchronised human pluripotent stem cell (hPSC) differentiation system for uncovering epigenome and transcriptome dynamics during the first two divisions leading to definitive endoderm. We observed that transcription of key differentiation markers occurs before cell division, while chromatin accessibility analyses revealed the early inhibition of alternative cell fates. We found that Activator protein-1 members controlled by p38/MAPK signalling are necessary for inducing endoderm while blocking cell fate shifting toward mesoderm, and that enhancers are rapidly established and decommissioned between different cell divisions. Our study has practical biomedical utility for producing hPSC-derived patient-specific cell types since p38/MAPK induction increased the differentiation efficiency of insulin-producing pancreatic beta-cells.


Asunto(s)
Células Madre Pluripotentes , Humanos , Diferenciación Celular/genética , Regulación de la Expresión Génica , Antígenos de Diferenciación/metabolismo , Epigénesis Genética , Endodermo
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