RESUMEN

The appropriate deployment of developmental programs depends on complex genetic information encoded by genomic DNA sequences and their positioning and contacts in the three-dimensional (3D) space within the nucleus. Current studies using novel techniques including, but not limited to, Hi-C, ChIA-PET, and Hi-ChIP reveal that regulatory elements (Res), such as enhancers and promoters, may participate in the precise regulation of expression of tissue-specific genes important for both embryogenesis and organogenesis by recruiting Polycomb Group (PcG) complexes. PcG complexes usually poise the transcription of developmental genes by forming Polycomb bodies to compact poised enhancers and promoters marked by H3K27me3 in the 3D space. Additionally, recent studies have also uncovered their roles in transcriptional activation. To better understand the full complexities in the mechanisms of how PcG complexes regulate transcription and long-range 3D contacts of enhancers and promoters during developmental programs, we outline novel insights regarding PcG-associated dramatic changes in the 3D chromatin conformation in developmental programs of early embryos and naïve-ground-state transitions of pluripotent embryonic stem cells (ESCs), and highlight the distinct roles of unique and common subunits of canonical and non-canonical PcG complexes in shaping genome architectures and transcriptional programs.

Asunto(s)

Cromatina , Proteínas de Drosophila , Cromatina/genética , Proteínas del Grupo Polycomb/genética , Proteínas del Grupo Polycomb/metabolismo , Cromosomas/metabolismo , Desarrollo Embrionario/genética , Proteínas de Drosophila/genética

RESUMEN

Populations of resident stem cells (SCs) are responsible for maintaining, repairing, and regenerating adult tissues. In addition to having the capacity to generate all the differentiated cell types of the tissue, adult SCs undergo long periods of quiescence within the niche to maintain themselves. The process of SC renewal and differentiation is tightly regulated for proper tissue regeneration throughout an organisms' lifetime. Epigenetic regulators, such as the polycomb group (PcG) of proteins have been implicated in modulating gene expression in adult SCs to maintain homeostatic and regenerative balances in adult tissues. In this review, we summarize the recent findings that elucidate the composition and function of the polycomb repressive complex machinery and highlight their role in diverse adult stem cell compartments.

Asunto(s)

Epigénesis Genética/genética , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 2/genética , Proteínas del Grupo Polycomb/genética , Células Madre Adultas/citología , Diferenciación Celular/genética , Autorrenovación de las Células/genética , Humanos

RESUMEN

Merkel cells are specialized epithelial cells connected to afferent nerve endings responsible for light-touch sensations, formed at specific locations in touch-sensitive regions of the mammalian skin. Although Merkel cells are descendants of the epidermal lineage, little is known about the mechanisms responsible for the development of these unique mechanosensory cells. Recent studies have highlighted that the Polycomb group (PcG) of proteins play a significant role in spatiotemporal regulation of Merkel cell formation. In addition, several of the major signalling pathways involved in skin development have been shown to regulate Merkel cell development as well. Here, we summarize the current understandings of the role of developmental regulators in Merkel cell formation, including the interplay between the epigenetic machinery and key signalling pathways, and the lineage-specific transcription factors involved in the regulation of Merkel cell development.

Asunto(s)

Epigénesis Genética , Células de Merkel/metabolismo , Proteínas del Grupo Polycomb/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Animales , Linaje de la Célula/genética , Humanos , Ratones , Transducción de Señal/genética

RESUMEN

Non-coding RNAs (ncRNAs) play important and diverse roles in mammalian cell biology and pathology. Although the functions of an increasing number of ncRNAs have been identified, the mechanisms underlying ncRNA gene expression remain elusive and are incompletely understood. Here, we investigated ncRNA gene expression in Michigan cancer foundation 7 (MCF7), a malignant breast cancer cell line, on treatment of tetraarsenic oxide (TAO), a potential anti-cancer drug. Our genomic analyses found that TAO up- or down-regulated ncRNA genes genome-wide. A subset of identified ncRNAs with critical biological and clinical functions were validated by real-time quantitative polymerase chain reaction. Intriguingly, these TAO-regulated genes included CDKN2B-AS, HOXA11-AS, SHH, and DUSP5 that are known to interact with or be targeted by polycomb repressive complexes (PRCs). In addition, the PRC subunits were enriched in these TAO-regulated ncRNA genes and TAO treatment deregulated the expression of PRC subunits. Strikingly, TAO decreased the cellular and gene-specific levels of EZH2 expression and H3K27me3. In particular, TAO reduced EZH2 and H3K27me3 and increased transcription at MALAT1 gene. Inhibiting the catalytic activity of EZH2 using GSK343 increased representative TAO-inducible ncRNA genes. Together, our findings suggest that the expression of a subset of ncRNA genes is regulated by PRC2 and that TAO could be a potent epigenetic regulator through PRCs to modulate the ncRNA gene expression in MCF7 cells.

Asunto(s)

Antineoplásicos/farmacología , Trióxido de Arsénico/farmacología , Histonas/genética , Proteínas del Grupo Polycomb/genética , ARN no Traducido/genética , Transcriptoma , Autofagia/efectos de los fármacos , Autofagia/genética , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Biología Computacional/métodos , Reparación del ADN/efectos de los fármacos , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Exocitosis/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Ontología de Genes , Genoma Humano , Células HEK293 , Histonas/metabolismo , Humanos , Células MCF-7 , Anotación de Secuencia Molecular , Proteínas del Grupo Polycomb/clasificación , Proteínas del Grupo Polycomb/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN no Traducido/clasificación , ARN no Traducido/metabolismo

RESUMEN

Depletion of architectural factors globally alters chromatin structure but only modestly affects gene expression. We revisit the structure-function relationship using the inactive X chromosome (Xi) as a model. We investigate cohesin imbalances by forcing its depletion or retention using degron-tagged RAD21 (cohesin subunit) or WAPL (cohesin release factor). Cohesin loss disrupts the Xi superstructure, unveiling superloops between escapee genes with minimal effect on gene repression. By contrast, forced cohesin retention markedly affects Xi superstructure, compromises spreading of Xist RNA-Polycomb complexes, and attenuates Xi silencing. Effects are greatest at distal chromosomal ends, where looping contacts with the Xist locus are weakened. Surprisingly, cohesin loss creates an Xi superloop, and cohesin retention creates Xi megadomains on the active X chromosome. Across the genome, a proper cohesin balance protects against aberrant inter-chromosomal interactions and tempers Polycomb-mediated repression. We conclude that a balance of cohesin eviction and retention regulates X inactivation and inter-chromosomal interactions across the genome.

Asunto(s)

Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Células Madre Embrionarias/metabolismo , Silenciador del Gen , Proteínas del Grupo Polycomb/metabolismo , ARN Largo no Codificante/metabolismo , Inactivación del Cromosoma X , Cromosoma X , Animales , Proteínas de Ciclo Celular/genética , Línea Celular , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Ratones , Conformación de Ácido Nucleico , Proteínas del Grupo Polycomb/genética , Conformación Proteica , Proteínas/genética , Proteínas/metabolismo , ARN Largo no Codificante/genética , Relación Estructura-Actividad , Cohesinas

RESUMEN

High-throughput sequencing has facilitated the identification of many types of non-coding RNAs (ncRNAs) involved in diverse cellular processes. NcRNAs as epigenetic mediators play key roles in neuronal development, maintenance, and dysfunction by controlling gene expression at multiple levels. NcRNAs may not only target specific DNA or RNA for gene silence but may also directly interact with chromatin-modifying proteins like Polycomb group (PcG) proteins to drive orchestrated transcriptional programs. Recent significant progress has been made in characterizing ncRNAs and PcG proteins involved in transcriptional, post-transcriptional, and epigenetic regulation. More importantly, dysregulation of ncRNAs, PcG proteins, and interplay among them is closely associated with the pathogenesis of central nervous system (CNS) disorders. In this review, we focus on the interplay between ncRNAs and PcG proteins in the CNS and highlight the functional roles of the partnership during neural development and diseases.

Asunto(s)

Sistema Nervioso Central/metabolismo , Redes Reguladoras de Genes , Proteínas del Grupo Polycomb/metabolismo , ARN no Traducido/metabolismo , Animales , Epigénesis Genética , Humanos , ARN no Traducido/genética

RESUMEN

Mammalian chromosomes are partitioned into A/B compartments and topologically associated domains (TADs). The inactive X (Xi) chromosome, however, adopts a distinct conformation without evident compartments or TADs. Here, through exploration of an architectural protein, structural-maintenance-of-chromosomes hinge domain containing 1 (SMCHD1), we probe how the Xi is reconfigured during X chromosome inactivation. A/B compartments are first fused into "S1" and "S2" compartments, coinciding with Xist spreading into gene-rich domains. SMCHD1 then binds S1/S2 compartments and merges them to create a compartment-less architecture. Contrary to current views, TADs remain on the Xi but in an attenuated state. Ablating SMCHD1 results in a persistent S1/S2 organization and strengthening of TADs. Furthermore, loss of SMCHD1 causes regional defects in Xist spreading and erosion of heterochromatic silencing. We present a stepwise model for Xi folding, where SMCHD1 attenuates a hidden layer of Xi architecture to facilitate Xist spreading.

Asunto(s)

Proteínas Cromosómicas no Histona/metabolismo , Cromosomas de los Mamíferos/química , Inactivación del Cromosoma X , Alelos , Animales , Línea Celular , Proteínas Cromosómicas no Histona/genética , Cromosomas de los Mamíferos/metabolismo , Metilación de ADN , Femenino , Heterocromatina/metabolismo , Histonas/genética , Histonas/metabolismo , Masculino , Ratones , Células Madre Embrionarias de Ratones/citología , Células Madre Embrionarias de Ratones/metabolismo , Análisis de Componente Principal , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo

RESUMEN

Polycomb complexes are essential regulators of embryonic and adult stem cells, highly conserved from flies to mammals. Traditionally, their study was based on biochemical and genetic approaches. More recently, the development of novel technologies and the improvement and standardization of existing ones has allowed to address previously unexplored aspects of Polycomb biology, such as dynamics and regulation. In this chapter, relevant researchers in the field discuss novel technologies aimed at dissecting the dynamics of Polycomb complexes in normal and pathological conditions.

Asunto(s)

Proteínas de Drosophila/aislamiento & purificación , Transferencia Resonante de Energía de Fluorescencia/métodos , Proteínas del Grupo Polycomb/aislamiento & purificación , Transcripción Genética , Proteínas de Drosophila/genética , Células Madre Embrionarias , Regulación del Desarrollo de la Expresión Génica , Proteínas del Grupo Polycomb/genética

RESUMEN

The recent revolution in sequencing technology has helped to reveal a large transcriptome of long non-coding RNAs (lncRNAs). A major challenge in the years to come is to determine what biological functions, if any, they serve. Although the purpose of these transcripts is largely unknown at present, existing examples suggest that lncRNAs play roles in a wide variety of biological processes. Exemplary cases are lncRNAs within the X-inactivation center. Indeed, lncRNAs dominate control of random X-chromosome inactivation (XCI). The RNA-based regulatory mechanisms of XCI include recruitment of chromatin modifiers, formation of RNA-based subnuclear compartments, and regulation of transcription by antisense transcription. XCI and lncRNAs now also appear to be very relevant in the development and progression of cancer. This perspective focuses on new insights into lncRNA-dependent regulation of XCI, which we believe serve as paradigms for understanding lncRNA function more generally.

Asunto(s)

Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , ARN Largo no Codificante/genética , Inactivación del Cromosoma X/genética , Diferenciación Celular , ADN sin Sentido/genética , Silenciador del Gen , Humanos , Modelos Moleculares , Neoplasias/metabolismo , Proteínas del Grupo Polycomb/genética , Proteínas del Grupo Polycomb/metabolismo , Regiones Promotoras Genéticas , ARN Largo no Codificante/metabolismo , Transcriptoma , Regulación hacia Arriba