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1.
Genome Res ; 34(4): 539-555, 2024 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-38719469

RESUMEN

Estrogen Receptor 1 (ESR1; also known as ERα, encoded by ESR1 gene) is the main driver and prime drug target in luminal breast cancer. ESR1 chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ESR1 chromatin action, along with its biological implications. Here, we use a large set of ESR1 ChIP-seq data from 70 ESR1+ breast cancers to explore inter-patient heterogeneity in ESR1 DNA binding to reveal a striking inter-tumor heterogeneity of ESR1 action. Of note, commonly shared ESR1 sites show the highest estrogen-driven enhancer activity and are most engaged in long-range chromatin interactions. In addition, the most commonly shared ESR1-occupied enhancers are enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ESR1 and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we can confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ESR1-chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ESR1 landscape, with the most common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.


Asunto(s)
Neoplasias de la Mama , Cromatina , Elementos de Facilitación Genéticos , Receptor alfa de Estrógeno , Femenino , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Cromatina/metabolismo , Cromatina/genética , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Regulación Neoplásica de la Expresión Génica , Heterogeneidad Genética , Polimorfismo de Nucleótido Simple
2.
Nat Commun ; 12(1): 6967, 2021 11 29.
Artículo en Inglés | MEDLINE | ID: mdl-34845227

RESUMEN

Breast cancer is now globally the most frequent cancer and leading cause of women's death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ERα + ) phenotype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ERα-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ERα + breast cancer models. The ERα + phenotype is not stable in cultured cells for reasons not fully understood. We examine 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three-dimensional matrix scaffolds, finding that ERα is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ERα signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ERα phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions. Subject terms: ER-positive (ER + ), breast cancer, ex vivo model, preclinical model, PDEC, stiffness, p38 SAPK.


Asunto(s)
Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Mecanotransducción Celular/genética , Transcriptoma , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Cinamatos/farmacología , Colágeno/química , Colágeno/farmacología , Combinación de Medicamentos , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Estradiol/farmacología , Receptor alfa de Estrógeno/metabolismo , Femenino , Fulvestrant/farmacología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Histonas/genética , Histonas/metabolismo , Humanos , Indazoles/farmacología , Laminina/química , Laminina/farmacología , Glándulas Mamarias Humanas/efectos de los fármacos , Glándulas Mamarias Humanas/metabolismo , Glándulas Mamarias Humanas/patología , Fenotipo , Proteoglicanos/química , Proteoglicanos/farmacología , Tamoxifeno/farmacología , Técnicas de Cultivo de Tejidos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
3.
Sci Rep ; 11(1): 17587, 2021 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-34475492

RESUMEN

CXXC5 is a member of the zinc-finger CXXC family proteins that interact with unmodified CpG dinucleotides through a conserved ZF-CXXC domain. CXXC5 is involved in the modulation of gene expressions that lead to alterations in diverse cellular events. However, the underlying mechanism of CXXC5-modulated gene expressions remains unclear. Proteins perform their functions in a network of proteins whose identities and amounts change spatiotemporally in response to various stimuli in a lineage-specific manner. Since CXXC5 lacks an intrinsic transcription regulatory function or enzymatic activity but is a DNA binder, CXXC5 by interacting with proteins could act as a scaffold to establish a chromatin state restrictive or permissive for transcription. To initially address this, we utilized the proximity-dependent biotinylation approach. Proximity interaction partners of CXXC5 include DNA and chromatin modifiers, transcription factors/co-regulators, and RNA processors. Of these, CXXC5 through its CXXC domain interacted with EMD, MAZ, and MeCP2. Furthermore, an interplay between CXXC5 and MeCP2 was critical for a subset of CXXC5 target gene expressions. It appears that CXXC5 may act as a nucleation factor in modulating gene expressions. Providing a prelude for CXXC5 actions, our results could also contribute to a better understanding of CXXC5-mediated cellular processes in physiology and pathophysiology.


Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas de Unión al ADN/metabolismo , Factores de Transcripción/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteínas de Unión al ADN/genética , Femenino , Humanos , Células MCF-7 , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Dominios y Motivos de Interacción de Proteínas , Transducción de Señal , Factores de Transcripción/genética
4.
Sci Rep ; 11(1): 15655, 2021 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-34341443

RESUMEN

CXXC5 is a member of the zinc-finger CXXC family that binds to unmethylated CpG dinucleotides. CXXC5 modulates gene expressions resulting in diverse cellular events mediated by distinct signaling pathways. However, the mechanism responsible for CXXC5 expression remains largely unknown. We found here that of the 14 annotated CXXC5 transcripts with distinct 5' untranslated regions encoding the same protein, transcript variant 2 with the highest expression level among variants represents the main transcript in cell models. The DNA segment in and at the immediate 5'-sequences of the first exon of variant 2 contains a core promoter within which multiple transcription start sites are present. Residing in a region with high G-C nucleotide content and CpG repeats, the core promoter is unmethylated, deficient in nucleosomes, and associated with active RNA polymerase-II. These findings suggest that a CpG island promoter drives CXXC5 expression. Promoter pull-down revealed the association of various transcription factors (TFs) and transcription co-regulatory proteins, as well as proteins involved in histone/chromatin, DNA, and RNA processing with the core promoter. Of the TFs, we verified that ELF1 and MAZ contribute to CXXC5 expression. Moreover, the first exon of variant 2 may contain a G-quadruplex forming region that could modulate CXXC5 expression.


Asunto(s)
Islas de CpG , Proteínas de Unión al ADN , Factores de Transcripción , Metilación de ADN , Histonas/metabolismo , Transducción de Señal , Dedos de Zinc
5.
Bioinformatics ; 37(22): 4238-4239, 2021 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-33999190

RESUMEN

MOTIVATION: Next generation sequencing enabled the fast accumulation of genomic data at public repositories. This technology also made it possible to better understand the regulation of gene expression by transcription factors (TFs) and various chromatin-associated proteins through the integration of chromatin immunoprecipitation (ChIP-Seq). The Cistrome Project has become one of the indispensable research portals for biologists to access and analyze data generated with thousands of ChIP-Seq experiments. Integrative motif analysis on shared binding regions among a set of experiments is not yet achievable despite a set of search and analysis tools provided by Cistrome via its web interface and the Galaxy framework. RESULTS: We implemented a python command-line tool for searching binding sequences of a TF common to multiple ChIP-Seq experiments. We use the peaks in the Cistrome database as identified by MACS 2.0 for each experiment and identify shared peak regions in a genomic locus of interest. We then scan these regions for binding sequences using a binding motif of a TF obtained from the JASPAR database. MotifGenie is developed in collaboration with molecular biologists and its findings are corroborated by laboratory experiments. AVAILABILITY AND IMPLEMENTATION: MotifGenie is freely available at https://github.com/ceragoguztuzun/MotifGenie.


Asunto(s)
Secuenciación de Inmunoprecipitación de Cromatina , Factores de Transcripción , Análisis de Secuencia de ADN , Sitios de Unión/genética , Inmunoprecipitación de Cromatina , Factores de Transcripción/metabolismo
6.
Front Biosci (Landmark Ed) ; 24(2): 245-276, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-30468654

RESUMEN

17beta-estradiol (E2), the main circulating estrogen hormone, is involved in a wide variety of physiological functions ranging from the development to the maintenance of many tissues and organs. The effects of E2 on cells are primarily conveyed by the transcription factors, estrogen receptor (ER) alpha and beta. The regulation of responsive genes by the well-defined ER alpha in response to E2 relies on complex and highly organized processes that dynamically integrate functions of many transcription regulators to induce spatiotemporal alterations in chromatin state and structure. Changes in gene expressions result in cell-specific responses that include proliferation, differentiation and death. Deregulation of E2-ER alpha signaling contributes to the initiation and progression of target tissue malignancies. We aim here to provide a review of recent findings on dynamic transcriptional events mediated by E2-ER alpha with the anticipation that a better understanding of complex regulatory mechanisms underlying ER actions would be a critical basis for the development of effective prognostic tools for and therapeutic interventions against estrogen target tissue malignancies.


Asunto(s)
Estradiol/farmacología , Receptor alfa de Estrógeno/metabolismo , Elementos de Respuesta/genética , Transcripción Genética/efectos de los fármacos , Animales , Sitios de Unión/genética , Estradiol/sangre , Receptor alfa de Estrógeno/química , Humanos , Modelos Moleculares , Conformación de Ácido Nucleico , Dominios Proteicos
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