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1.
Genome Res ; 29(10): 1733-1743, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31533978

RESUMEN

Cellular identity relies on cell-type-specific gene expression controlled at the transcriptional level by cis-regulatory elements (CREs). CREs are unevenly distributed across the genome, giving rise to individual CREs and clusters of CREs (COREs). Technical and biological features hinder CORE identification. We addressed these issues by developing an unsupervised machine learning approach termed clustering of genomic regions analysis method (CREAM). CREAM automates CORE detection from chromatin accessibility profiles that are enriched in CREs strongly bound by master transcription regulators, proximal to highly expressed and essential genes, and discriminating cell identity. Although COREs share similarities with super-enhancers, we highlight differences in terms of the genomic distribution and structure of these cis-regulatory units. We further show the enhanced value of COREs over super-enhancers to identify master transcription regulators, highly expressed and essential genes defining cell identity. COREs enrich at topologically associated domain (TAD) boundaries. They are also preferentially bound by the chromatin looping factors CTCF and cohesin, in contrast to super-enhancers, forming clusters of CTCF and cohesin binding regions and defining homotypic clusters of transcription regulator binding regions (HCTs). Finally, we show the clinical utility of CREAM to identify COREs across chromatin accessibility profiles to stratify more than 400 tumor samples according to their cancer type and to delineate cancer type-specific active biological pathways. Collectively, our results support the utility of CREAM to delineate COREs underlying, with greater accuracy than individual CREs or super-enhancers, the cell-type-specific biological underpinning across a wide range of normal and cancer cell types.


Asunto(s)
Factor de Unión a CCCTC/genética , Elementos de Facilitación Genéticos , Neoplasias/genética , Elementos Reguladores de la Transcripción/genética , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Linaje de la Célula/genética , Cromatina/genética , Proteínas Cromosómicas no Histona/genética , Regulación de la Expresión Génica/genética , Genómica , Humanos , Cohesinas
2.
Genome Res ; 27(6): 985-996, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28400425

RESUMEN

Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TRs). However, how recruitment of a myriad of TRs is orchestrated at cis-regulatory modules (CRMs) to account for coregulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRMs involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question. Using integrative cistromic, epigenomic, transcriptomic, and interactomic analyses, we reveal a logical organization where trans-regulatory modules (TRMs), which consist of subsets of preferentially and coordinately corecruited TRs, assemble into hierarchical combinations at hepatic CRMs. Different combinations of TRMs add to a core TRM, broadly found across the whole landscape of CRMs, to discriminate promoters from enhancers. These combinations also specify distinct sets of CRM differentially organized along the genome and involved in regulation of either housekeeping/cellular maintenance genes or liver-specific functions. In addition to these TRMs which we define as obligatory, we show that facultative TRMs, such as one comprising core circadian TRs, are further recruited to selective subsets of CRMs to modulate their activities. TRMs transcend TR classification into ubiquitous versus liver-identity factors, as well as TR grouping into functional families. Hence, hierarchical superimpositions of obligatory and facultative TRMs bring about independent transcriptional regulatory inputs defining different sets of CRMs with logical connection to regulation of specific gene sets and biological pathways. Altogether, our study reveals novel principles of concerted transcriptional regulation by multiple TRs at CRMs.


Asunto(s)
Genoma , Hígado/metabolismo , Elementos Reguladores de la Transcripción , Transcripción Genética , Algoritmos , Animales , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Genómica/métodos , Ratones , Ratones Noqueados , PPAR alfa/deficiencia , PPAR alfa/genética , Receptores Citoplasmáticos y Nucleares/deficiencia , Receptores Citoplasmáticos y Nucleares/genética
3.
Mol Cancer Res ; 20(1): 102-113, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34556523

RESUMEN

Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and noncoding cancer driver plexuses from somatic mutations. However, differentiating driver from passenger events among noncoding genetic variants remains a challenge. Herein, we reveal cancer-driver cis-regulatory elements linked to transcription factors previously shown to be involved in development of luminal breast cancers by defining a tumor-enriched catalogue of approximately 100,000 unique cis-regulatory elements from 26 primary luminal estrogen receptor (ER)+ progesterone receptor (PR)+ breast tumors. Integrating this catalog with somatic mutations from 350 publicly available breast tumor whole genomes, we uncovered cancer driver cistromes, defined as the sum of binding sites for a transcription factor, for ten transcription factors in luminal breast cancer such as FOXA1 and ER, nine of which are essential for growth in breast cancer with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of noncoding mutations over cis-regulatory elements concatenated into a functional unit. IMPLICATIONS: Mapping the accessible chromatin of luminal breast cancer led to discovery of an accumulation of mutations within cistromes of transcription factors essential to luminal breast cancer. This demonstrates coopting of regulatory networks to drive cancer and provides a framework to derive insight into the noncoding space of cancer.


Asunto(s)
Neoplasias de la Mama/genética , Cromatina/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Secuenciación Completa del Genoma/métodos , Neoplasias de la Mama/patología , Femenino , Humanos , Mutación
4.
Science ; 378(6615): 68-78, 2022 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-36201590

RESUMEN

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1R132H-driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.


Asunto(s)
Neoplasias Encefálicas , Cromosomas Humanos Par 8 , Glioma , Isocitrato Deshidrogenasa , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Cromosomas Humanos Par 8/genética , Glioma/genética , Glioma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Ratones , Mutación , Polimorfismo de Nucleótido Simple
5.
Nat Commun ; 12(1): 1781, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741908

RESUMEN

Prostate cancer (PCa) risk-associated SNPs are enriched in noncoding cis-regulatory elements (rCREs), yet their modi operandi and clinical impact remain elusive. Here, we perform CRISPRi screens of 260 rCREs in PCa cell lines. We find that rCREs harboring high risk SNPs are more essential for cell proliferation and H3K27ac occupancy is a strong indicator of essentiality. We also show that cell-line-specific essential rCREs are enriched in the 8q24.21 region, with the rs11986220-containing rCRE regulating MYC and PVT1 expression, cell proliferation and tumorigenesis in a cell-line-specific manner, depending on DNA methylation-orchestrated occupancy of a CTCF binding site in between this rCRE and the MYC promoter. We demonstrate that CTCF deposition at this site as measured by DNA methylation level is highly variable in prostate specimens, and observe the MYC eQTL in the 8q24.21 locus in individuals with low CTCF binding. Together our findings highlight a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture, advocating for the integration of genetics and epigenetics in assessing risks conferred by genetic predispositions.


Asunto(s)
Sistemas CRISPR-Cas , Metilación de ADN , Edición Génica/métodos , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Neoplasias de la Próstata/genética , Animales , Factor de Unión a CCCTC/genética , Factor de Unión a CCCTC/metabolismo , Carcinogénesis/genética , Línea Celular Tumoral , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-myc/genética , Sitios de Carácter Cuantitativo/genética , Elementos Reguladores de la Transcripción/genética , Factores de Riesgo
6.
Nat Commun ; 11(1): 441, 2020 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-31974375

RESUMEN

Prostate cancer is the second most commonly diagnosed malignancy among men worldwide. Recurrently mutated in primary and metastatic prostate tumors, FOXA1 encodes a pioneer transcription factor involved in disease onset and progression through both androgen receptor-dependent and androgen receptor-independent mechanisms. Despite its oncogenic properties however, the regulation of FOXA1 expression remains unknown. Here, we identify a set of six cis-regulatory elements in the FOXA1 regulatory plexus harboring somatic single-nucleotide variants in primary prostate tumors. We find that deletion and repression of these cis-regulatory elements significantly decreases FOXA1 expression and prostate cancer cell growth. Six of the ten single-nucleotide variants mapping to FOXA1 regulatory plexus significantly alter the transactivation potential of cis-regulatory elements by modulating the binding of transcription factors. Collectively, our results identify cis-regulatory elements within the FOXA1 plexus mutated in primary prostate tumors as potential targets for therapeutic intervention.


Asunto(s)
Factor Nuclear 3-alfa del Hepatocito/genética , Mutación , Neoplasias de la Próstata/genética , Secuencias Reguladoras de Ácidos Nucleicos , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Factores de Transcripción/metabolismo
7.
Cancer Cell ; 36(6): 674-689.e6, 2019 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-31735626

RESUMEN

Thousands of noncoding somatic single-nucleotide variants (SNVs) of unknown function are reported in tumors. Partitioning the genome according to cistromes reveals the enrichment of somatic SNVs in prostate tumors as opposed to adjacent normal tissue cistromes of master transcription regulators, including AR, FOXA1, and HOXB13. This parallels enrichment of prostate cancer genetic predispositions over these transcription regulators' tumor cistromes, exemplified at the 8q24 locus harboring both risk variants and somatic SNVs in cis-regulatory elements upregulating MYC expression. However, Massively Parallel Reporter Assays reveal that few SNVs can alter the transactivation potential of individual cis-regulatory elements. Instead, similar to inherited risk variants, SNVs accumulate in cistromes of master transcription regulators required for prostate cancer development.


Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Proteínas de Homeodominio/metabolismo , Neoplasias de la Próstata/metabolismo , Línea Celular Tumoral , Proteínas de Homeodominio/genética , Humanos , Masculino , Mutación/genética , Neoplasias de la Próstata/patología , Regulación hacia Arriba/genética
8.
Transcription ; 9(4): 233-239, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29105538

RESUMEN

Gene transcriptional regulation relies on cis-regulatory DNA modules (CRMs), which serve as nexus sites for integration of multiple transcription factor (TF) activities. Here, we provide evidence and discuss recent literature indicating that TF recruitment to CRMs is organized into combinations of trans-regulatory protein modules (TRMs). We propose that TRMs are functional entities composed of TFs displaying the most highly interdependent chromatin binding which are, in addition, able to modulate their recruitment to CRMs through inter-TRM effects. These findings shed light on the architectural organization of TF recruitment encoded by their recognition motifs within CRMs.


Asunto(s)
Regulación de la Expresión Génica/genética , Elementos Reguladores de la Transcripción/genética , Factores de Transcripción/metabolismo , Animales , ADN/genética , ADN/metabolismo , Humanos
9.
Nat Genet ; 48(10): 1260-6, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27571262

RESUMEN

Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer risk-associated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer.


Asunto(s)
Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Mutación , Polimorfismo de Nucleótido Simple , Sistemas CRISPR-Cas , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Secuencias Reguladoras de Ácidos Nucleicos , Factores de Transcripción/metabolismo
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