Gene Regulation by Cohesin in Cancer: Is the Ring an Unexpected Party to Proliferation?

Rhodes, Jenny M.; McEwan, Miranda; Horsfield, Julia A.

doi:10.1158/1541-7786.mcr-11-0382

Cited by 41 publications

(49 citation statements)

References 162 publications

(214 reference statements)

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“…The target genes of TFs in this cluster are preferentially up-regulated in most cancer types, which indicates these TFs as pervasive oncogenic regulators. Another example, RAD21, a member of the cohesion complex with important roles in chromosome maintenance (22), has its target genes repressed in breast cancer (BRCA) (Fig. 2 and SI Appendix, Fig.…”

Section: Significancementioning

confidence: 99%

Inference of transcriptional regulation in cancers

Jiang

Freedman

et al. 2015

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

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Despite the rapid accumulation of tumor-profiling data and transcription factor (TF) ChIP-seq profiles, efforts integrating TF binding with the tumor-profiling data to understand how TFs regulate tumor gene expression are still limited. To systematically search for cancerassociated TFs, we comprehensively integrated 686 ENCODE ChIPseq profiles representing 150 TFs with 7484 TCGA tumor data in 18 cancer types. For efficient and accurate inference on gene regulatory rules across a large number and variety of datasets, we developed an algorithm, RABIT (regression analysis with background integration). In each tumor sample, RABIT tests whether the TF target genes from ChIP-seq show strong differential regulation after controlling for background effect from copy number alteration and DNA methylation. When multiple ChIP-seq profiles are available for a TF, RABIT prioritizes the most relevant ChIP-seq profile in each tumor. In each cancer type, RABIT further tests whether the TF expression and somatic mutation variations are correlated with differential expression patterns of its target genes across tumors. Our predicted TF impact on tumor gene expression is highly consistent with the knowledge from cancer-related gene databases and reveals many previously unidentified aspects of transcriptional regulation in tumor progression. We also applied RABIT on RNAbinding protein motifs and found that some alternative splicing factors could affect tumor-specific gene expression by binding to target gene 3′UTR regions. Thus, RABIT (rabit.dfci.harvard.edu) is a general platform for predicting the oncogenic role of gene expression regulators.regulatory inference | tumor profiling | transcription factor | RNA-binding proteinT umorigenesis is a multistep process requiring alterations in gene expression programs (1, 2). Transcription factors (TFs) are instrumental in driving these gene expression programs, and misregulation of these TFs can result in the acquisition of tumorrelated properties (3). For example, E2F1 is overexpressed in many cancer types and promotes tumor proliferation by regulating expression of genes involved in cell differentiation, metabolism, and development (4). As another example, FOXM1 plays an important role in promoting cell proliferation and cell cycle progression through transcriptional activation of many G2/M-specific genes. Increased FOXM1 gene expression was detected in numerous cancer types, and FOXM1 is a promising therapeutic target for cancer treatment (5). TFs also play critical roles in inducing the tumor microenvironment for metastasis. For example, SNAI1/2, TWIST, and ZEB1/2 orchestrate the expression of genes involved in cell polarity, cell-cell contact, cytoskeleton structure, and extracellular matrix degradation. The joint effect of these TFs promotes cancer cell motility and invasion in the metastatic process (2, 6).With the rapid development of high-throughput technologies, large amounts of datasets have been generated for regulatory proteins. For example, the ENCODE project generated 689 C...

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Section: Significancementioning

confidence: 99%

Inference of transcriptional regulation in cancers

Jiang

Freedman

et al. 2015

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

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“…In addition to its canonical function in sister chromatid cohesion and separation, cohesin and its associating-proteins are major players in gene transcription and development. [76][77][78] Therefore, Sororin's role in gene expression would be an area of great interest. Furthermore, Sororin's role in DNA replication is also an emerging area of research.…”

Section: Concluding Remarkmentioning

confidence: 99%

Sororin is a master regulator of sister chromatid cohesion and separation

Zhang

Pati

2012

Cell Cycle

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“…Furthermore, depletion of the cohesin subunit SMC3 significantly impaired the estrogenregulated transcriptome. 43 Taken together, these findings suggest that cohesin modifies the higher-order structure of chromatin in estrogen pathway-related genes and serves toward establishment of the correct pattern of gene expression. Although most of these effects of estrogen were observed in oncogenic models, 39 similar processes may affect normal bone growth and development and are awaiting to be characterized.…”

Section: Possible Involvement Of Smcs In Molecular Pathways Of Bone Dmentioning

confidence: 84%

“…Cohesin binds chromatin and regulates gene expression in response to estrogen [40][41][42]43 TNF-a An inflammatory cytokine involved in immunity and inflammation…”

Section: Esr1mentioning

confidence: 99%

Structural maintenance of chromosome complexes and bone development: the beginning of a wonderful relationship?

Cohen-Zinder¹,

Karasik

Onn

2013

BoneKEy Reports

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Bone development depends on environmental, nutritional and hormonal factors. Yet, an ordered and timed activation of genes and their associated molecular pathways are central for the growth and development of healthy bones. The correct expression of genes depends on both cis-and trans-regulatory elements. Of these, the elusive role of chromatin ultrastructure is just beginning to become appreciated. Changes in the higher-order structure of chromatin are affecting the expression of genes in response to intrinsic and environmental signals. Cohesin and condensin are members of the structural maintenance of chromosome (SMC) family of protein complexes, which mediate higher-order chromatin structure by tethering distinct regions of chromatin either inter-or intra-molecularly. In recent years, SMCs had been identified for their function in the regulation of gene expression and developmental processes, whereas malfunction of cohesin or condensin has an impact on human health. However, little is known about the specific roles of SMC complexes in bone development and their possible effect on bone health. Here, we review studies that suggest an intimate link between SMCs and bone development, as well as a plausible effect, direct or indirect, on the bone health. We describe genetic syndromes associated with SMCs with distinctive bone phenotypes and identify links between SMCs and bone-related molecular pathways. Future studies of the relationship between SMCs and bone development will reveal new understandings of both the cellular and molecular roles of SMC complexes and provide new insights into the growth and developmental processes in the bone.

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Gene Regulation by Cohesin in Cancer: Is the Ring an Unexpected Party to Proliferation?

Cited by 41 publications

References 162 publications

Inference of transcriptional regulation in cancers

Inference of transcriptional regulation in cancers

Sororin is a master regulator of sister chromatid cohesion and separation

Structural maintenance of chromosome complexes and bone development: the beginning of a wonderful relationship?

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