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  1. Article ; Online: ChIPr

    Ahmed Abbas / Khyati Chandratre / Yunpeng Gao / Jiapei Yuan / Michael Q. Zhang / Ram S. Mani

    Genome Biology, Vol 25, Iss 1, Pp 1-

    accurate prediction of cohesin-mediated 3D genome organization from 2D chromatin features

    2024  Volume 27

    Abstract: Abstract The three-dimensional genome organization influences diverse nuclear processes. Here we present Chromatin Interaction Predictor (ChIPr), a suite of regression models based on deep neural networks, random forest, and gradient boosting to predict ... ...

    Abstract Abstract The three-dimensional genome organization influences diverse nuclear processes. Here we present Chromatin Interaction Predictor (ChIPr), a suite of regression models based on deep neural networks, random forest, and gradient boosting to predict cohesin-mediated chromatin interaction strength between any two loci in the genome. The predictions of ChIPr correlate well with ChIA-PET data in four cell lines. The standard ChIPr model requires three experimental inputs: ChIP-Seq signals for RAD21, H3K27ac, and H3K27me3 but works well with just RAD21 signal. Integrative analysis reveals novel insights into the role of CTCF motif, its orientation, and CTCF binding on cohesin-mediated chromatin interactions.
    Keywords Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer

    Shahanshah Khan / Youn-Tae Kwak / Lan Peng / Shuiqing Hu / Brandi L. Cantarel / Cheryl M. Lewis / Yunpeng Gao / Ram S. Mani / Thirumala-Devi Kanneganti / Hasan Zaki

    The Journal of Clinical Investigation, Vol 133, Iss

    2023  Volume 19

    Abstract: Colorectal cancer (CRC) at advanced stages is rarely curable, underscoring the importance of exploring the mechanism of CRC progression and invasion. NOD-like receptor family member NLRP12 was shown to suppress colorectal tumorigenesis, but the precise ... ...

    Abstract Colorectal cancer (CRC) at advanced stages is rarely curable, underscoring the importance of exploring the mechanism of CRC progression and invasion. NOD-like receptor family member NLRP12 was shown to suppress colorectal tumorigenesis, but the precise mechanism was unknown. Here, we demonstrate that invasive adenocarcinoma development in Nlrp12-deficient mice is associated with elevated expression of genes involved in proliferation, matrix degradation, and epithelial-mesenchymal transition. Signaling pathway analysis revealed higher activation of the Wnt/β-catenin pathway, but not NF-κB and MAPK pathways, in the Nlrp12-deficient tumors. Using Nlrp12–conditional knockout mice, we revealed that NLRP12 downregulates β-catenin activation in intestinal epithelial cells, thereby suppressing colorectal tumorigenesis. Consistent with this, Nlrp12-deficient intestinal organoids and CRC cells showed increased proliferation, accompanied by higher activation of β-catenin in vitro. With proteomic studies, we identified STK38 as an interacting partner of NLRP12 involved in the inhibition of phosphorylation of GSK3β, leading to the degradation of β-catenin. Consistently, the expression of NLRP12 was significantly reduced, while p-GSK3β and β-catenin were upregulated in mouse and human colorectal tumor tissues. In summary, NLRP12 is a potent negative regulator of the Wnt/β-catenin pathway, and the NLRP12/STK38/GSK3β signaling axis could be a promising therapeutic target for CRC.
    Keywords Gastroenterology ; Medicine ; R
    Subject code 570
    Language English
    Publishing date 2023-10-01T00:00:00Z
    Publisher American Society for Clinical Investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: FOXA2 suppresses endometrial carcinogenesis and epithelial-mesenchymal transition by regulating enhancer activity

    Subhransu S. Sahoo / Susmita G. Ramanand / Yunpeng Gao / Ahmed Abbas / Ashwani Kumar / Ileana C. Cuevas / Hao-Dong Li / Mitzi Aguilar / Chao Xing / Ram S. Mani / Diego H. Castrillon

    The Journal of Clinical Investigation, Vol 132, Iss

    2022  Volume 12

    Abstract: FOXA2 encodes a transcription factor mutated in 10% of endometrial cancers (ECs), with a higher mutation rate in aggressive variants. FOXA2 has essential roles in embryonic and uterine development. However, FOXA2’s role in EC is incompletely understood. ... ...

    Abstract FOXA2 encodes a transcription factor mutated in 10% of endometrial cancers (ECs), with a higher mutation rate in aggressive variants. FOXA2 has essential roles in embryonic and uterine development. However, FOXA2’s role in EC is incompletely understood. Functional investigations using human and mouse EC cell lines revealed that FOXA2 controls endometrial epithelial gene expression programs regulating cell proliferation, adhesion, and endometrial-epithelial transition. In live animals, conditional inactivation of Foxa2 or Pten alone in endometrial epithelium did not result in ECs, but simultaneous inactivation of both genes resulted in lethal ECs with complete penetrance, establishing potent synergism between Foxa2 and PI3K signaling. Studies in tumor-derived cell lines and organoids highlighted additional invasion and cell growth phenotypes associated with malignant transformation and identified key mediators, including Myc and Cdh1. Transcriptome and cistrome analyses revealed that FOXA2 broadly controls gene expression programs through modification of enhancer activity in addition to regulating specific target genes, rationalizing its tumor suppressor functions. By integrating results from our cell lines, organoids, animal models, and patient data, our findings demonstrated that FOXA2 is an endometrial tumor suppressor associated with aggressive disease and with shared commonalities among its roles in endometrial function and carcinogenesis.
    Keywords Oncology ; Medicine ; R
    Subject code 572 ; 570
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher American Society for Clinical Investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Targeting ESR1 mutation–induced transcriptional addiction in breast cancer with BET inhibition

    Sm N. Udden / Qian Wang / Sunil Kumar / Venkat S. Malladi / Shwu-Yuan Wu / Shuguang Wei / Bruce A. Posner / Sophie Geboers / Noelle S. Williams / Yulun Liu / Jayesh K. Sharma / Ram S. Mani / Srinivas Malladi / Karla Parra / Mia Hofstad / Ganesh V. Raj / Jose M. Larios / Reshma Jagsi / Max S. Wicha /
    Ben Ho Park / Gaorav P. Gupta / Arul M. Chinnaiyan / Cheng-Ming Chiang / Prasanna G. Alluri

    JCI Insight, Vol 7, Iss

    2022  Volume 17

    Abstract: Acquired mutations in the ligand-binding domain (LBD) of the gene encoding estrogen receptor α (ESR1) are common mechanisms of endocrine therapy resistance in patients with metastatic ER+ breast cancer. The ESR1 Y537S mutation, in particular, is ... ...

    Abstract Acquired mutations in the ligand-binding domain (LBD) of the gene encoding estrogen receptor α (ESR1) are common mechanisms of endocrine therapy resistance in patients with metastatic ER+ breast cancer. The ESR1 Y537S mutation, in particular, is associated with development of resistance to most endocrine therapies used to treat breast cancer. Employing a high-throughput screen of nearly 1,200 Federal Drug Administration–approved (FDA-approved) drugs, we show that OTX015, a bromodomain and extraterminal domain (BET) inhibitor, is one of the top suppressors of ESR1 mutant cell growth. OTX015 was more efficacious than fulvestrant, a selective ER degrader, in inhibiting ESR1 mutant xenograft growth. When combined with abemaciclib, a CDK4/6 inhibitor, OTX015 induced more potent tumor regression than current standard-of-care treatment of abemaciclib + fulvestrant. OTX015 has preferential activity against Y537S mutant breast cancer cells and blocks their clonal selection in competition studies with WT cells. Thus, BET inhibition has the potential to both prevent and overcome ESR1 mutant–induced endocrine therapy resistance in breast cancer.
    Keywords Oncology ; Medicine ; R
    Subject code 616 ; 610
    Language English
    Publishing date 2022-09-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer

    Xiangyi Li / GuemHee Baek / Susmita G. Ramanand / Adam Sharp / Yunpeng Gao / Wei Yuan / Jon Welti / Daniel N. Rodrigues / David Dolling / Ines Figueiredo / Semini Sumanasuriya / Mateus Crespo / Adam Aslam / Rui Li / Yi Yin / Bipasha Mukherjee / Mohammed Kanchwala / Ashley M. Hughes / Wendy S. Halsey /
    Cheng-Ming Chiang / Chao Xing / Ganesh V. Raj / Sandeep Burma / Johann de Bono / Ram S. Mani

    Cell Reports, Vol 22, Iss 3, Pp 796-

    2018  Volume 808

    Abstract: BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones and regulate gene expression. Pharmacological inhibition of BRD4 by BET inhibitors (BETi) has indicated antitumor activity against ... ...

    Abstract BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones and regulate gene expression. Pharmacological inhibition of BRD4 by BET inhibitors (BETi) has indicated antitumor activity against multiple cancer types. We show that BRD4 is essential for the repair of DNA double-strand breaks (DSBs) and mediates the formation of oncogenic gene rearrangements by engaging the non-homologous end joining (NHEJ) pathway. Mechanistically, genome-wide DNA breaks are associated with enhanced acetylation of histone H4, leading to BRD4 recruitment, and stable establishment of the DNA repair complex. In support of this, we also show that, in clinical tumor samples, BRD4 protein levels are negatively associated with outcome after prostate cancer (PCa) radiation therapy. Thus, in addition to regulating gene expression, BRD4 is also a central player in the repair of DNA DSBs, with significant implications for cancer therapy.
    Keywords BRD4 ; BRD2 ; DNA repair ; non-homologous end joining ; NHEJ ; gene fusion ; genomic rearrangements ; TMPRSS2-ERG ; prostate cancer ; CRPC ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2018-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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