Cistrome: an integrative platform for transcriptional regulation studies

Liu, Tao; Ortíz, Jorge; Taing, Len; Meyer, Clifford A.; Lee, Bernett; Zhang, Yong; Shin, Hyunjin; Wong, Suei Nee; Ma, Jian; Lei, Ying; Pape, Utz Johann; Poidinger, Michael; Chen, Yiwen; Yeung, Kevin; Brown, Myles; Turpaz, Yaron; Liu, X Shirley

doi:10.1186/gb-2011-12-8-r83

Cited by 643 publications

(619 citation statements)

References 39 publications

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“…Motifs enriched at ERα-binding sites were identified using SeqPos tools (with default settings) available through Galaxy Cistrome (28). Genes that had an ERα peak within the gene body or 20 kb upstream of the transcription start site (TSS) were identified as potential targets of the corresponding ERα-binding sites.…”

Section: Methodsmentioning

confidence: 99%

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Droog

Nevedomskaya

Dackus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The DNA-binding sites of estrogen receptor α (ERα) show great plasticity under the control of hormones and endocrine therapy. Tamoxifen is a widely applied therapy in breast cancer that affects ERα interactions with coregulators and shifts the DNA-binding signature of ERα upon prolonged exposure in breast cancer. Although tamoxifen inhibits the progression of breast cancer, it increases the risk of endometrial cancer in postmenopausal women. We therefore asked whether the DNA-binding signature of ERα differs between endometrial tumors that arise in the presence or absence of tamoxifen, indicating divergent enhancer activity for tumors that develop in different endocrine milieus. Using ChIP sequencing (ChIP-seq), we compared the ERα profiles of 10 endometrial tumors from tamoxifen users with those of six endometrial tumors from nonusers and integrated these results with the transcriptomic data of 47 endometrial tumors from tamoxifen users and 64 endometrial tumors from nonusers. The ERα-binding sites in tamoxifen-associated endometrial tumors differed from those in the tumors from nonusers and had distinct underlying DNA sequences and divergent enhancer activity as marked by histone 3 containing the acetylated lysine 27 (H3K27ac). Because tamoxifen acts as an agonist in the postmenopausal endometrium, similar to estrogen in the breast, we compared ERα sites in tamoxifen-associated endometrial cancers with publicly available ERα ChIP-seq data in breast tumors and found a striking resemblance in the ERα patterns of the two tissue types. Our study highlights the divergence between endometrial tumors that arise in different hormonal conditions and shows that ERα enhancer use in human cancer differs in the presence of nonphysiological endocrine stimuli.E strogen receptor α (ERα) is a steroid hormone receptor that behaves as a transcription factor by interacting with the DNA. The DNA-binding profile (cistrome) of ERα is dependent on context and tissue type (1). The hormonal environment of the cell greatly influences this cistrome because estrogen activates ERα by binding its ligand-binding domain. Upon activation, ERα's structural conformation changes to interact with cofactors at the DNA (2) and to regulate a transcriptional program that drives cell proliferation (3). Hence, the hormonal environment modulates the ERα cistrome and thereby rewires downstream effects.Endocrine therapies, as exemplified by tamoxifen, manipulate the DNA-binding capacities of the steroid hormone receptor ERα. Tamoxifen, a small-molecule inhibitor that competes with estrogens to bind ERα, is a major endocrine agent used in treating ERα-positive breast cancer patients. Studies in the breast cancer cell line MCF-7 show that prolonged tamoxifen exposure shifts the ERα cistrome, which consequently changes gene expression (4-6).Tamoxifen is a well-known selective estrogen receptor modulator (SERM) with tissue-selective physiological action. Early reports on tamoxifen's effects on transplanted MCF-7 cells in athymic mice revealed decreased tumor c...

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Section: Methodsmentioning

confidence: 99%

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Droog

Nevedomskaya

Dackus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…We then wished to determine whether H3K56ac presence is associated with the key transcriptional factors genome-wide. By comparing the correlation of H3K56ac and known transcription factors using our H3K56ac chromatin immunoprecipitation sequencing (ChIP-Seq) results and published data (4), we found using Cistrome (19) that H3K56ac correlates most positively with the presence of Oct4 and Sox2 and much less so with Nanog ( Fig. 1A; Pearson's correlation values in SI Appendix, Table S1).…”

Section: H3k56ac Presence Is Correlated With That Of Key Transcriptionalmentioning

confidence: 77%

Acetylated histone H3K56 interacts with Oct4 to promote mouse embryonic stem cell pluripotency

Tan

Xue

Song

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The presence of acetylated histone H3K56 (H3K56ac) in human ES cells (ESCs) correlates positively with the binding of Nanog, Sox2, and Oct4 (NSO) transcription factors at their target gene promoters. However, the function of H3K56ac there has been unclear. We now report that Oct4 interacts with H3K56ac in mouse ESC nuclear extracts and that perturbing H3K56 acetylation decreases Oct4-H3 binding. This interaction is likely to be direct because it can be recapitulated in vitro in an H3K56ac-dependent manner and is functionally important because H3K56ac combines with NSO factors in chromatin immunoprecipitation sequencing to mark the regions associated with pluripotency better than NSO alone. Moreover, reducing H3K56ac by short hairpin Asf1a decreases expression of pluripotency-related markers and increases expression of differentiation-related ones. Therefore, our data suggest that H3K56ac plays a central role in binding to Oct4 to promote the pluripotency of ESCs.

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“…Normalized Bigwig files were obtained using DeepTools 38 . Bioinformatics analyses were performed via the Cistrome platform 39 or Bioconductor 40 . Promoter reads were counted from -2000 to +2000 relative to the transcription start site and normalized to reads per million (rpm).…”

Section: Methodsmentioning

confidence: 99%

Polycomb-like proteins link the PRC2 complex to CpG islands

Liefke

Jiang

et al. 2017

Nature

261

323

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The Polycomb repressive complex 2 (PRC2) mainly mediates transcriptional repression1,2 and plays essential roles in various biological processes including the maintenance of cell identity and proper differentiation. Polycomb-like proteins (PCLs), including PHF1, MTF2 and PHF19, are PRC2 associated factors that form sub-complexes with PRC2 core components3, and have been proposed to modulate PRC2’s enzymatic activity or its recruitment to specific genomic loci4–13. Mammalian PRC2 binding sites are enriched in CG content, which correlate with CpG islands that display a low level of DNA methylation14. However, the mechanism of PRC2 recruitment to CpG islands is not fully understood. In this study, we solved the crystal structures of the N-terminal domains of PHF1 and MTF2 with bound CpG-containing DNAs in the presence of H3K36me3-containing histone peptides. We found that the extended homologous (EH) regions of both proteins fold into a winged-helix structure, which specifically binds to the unmethylated CpG motif but in a manner completely different from the canonical winged-helix motif-DNA recognition. We further showed that the PCL EH domains are required for efficient recruitment of PRC2 to CpG island-containing promoters in mouse embryonic cells. Our research provides the first direct evidence demonstrating that PCLs are critical for PRC2 recruitment to CpG islands, thereby further clarifying their roles in transcriptional regulation in vivo.

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Cistrome: an integrative platform for transcriptional regulation studies

Cited by 643 publications

References 39 publications

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Acetylated histone H3K56 interacts with Oct4 to promote mouse embryonic stem cell pluripotency

Polycomb-like proteins link the PRC2 complex to CpG islands

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