Browsing by Author "Hebbar, P."

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    An Enhancer-Driven Stem Cell–Like Program Mediated by SOX9 Blocks Intestinal Differentiation in Colorectal Cancer
    (W.B. Saunders, 2022) Liang, X.; Duronio, G.N.; Yang, Y.; Bala, P.; Hebbar, P.; Spisák, S.; Sahgal, P.; Singh, H.; Zhang, Y.; Xie, Y.; Cejas, P.; Long, H.W.; Bass, A.J.; Sethi, N.S.
    Background and Aims: Genomic alterations that encourage stem cell activity and hinder proper maturation are central to the development of colorectal cancer (CRC). Key molecular mediators that promote these malignant properties require further elucidation to galvanize translational advances. We therefore aimed to characterize a key factor that blocks intestinal differentiation, define its transcriptional and epigenetic program, and provide preclinical evidence for therapeutic targeting in CRC. Methods: Intestinal tissue from transgenic mice and patients were analyzed by means of histopathology and immunostaining. Human CRC cells and neoplastic murine organoids were genetically manipulated for functional studies. Gene expression profiling was obtained through RNA sequencing. Histone modifications and transcription factor binding were determined with the use of chromatin immunoprecipitation sequencing. Results: We demonstrate that SRY-box transcription factor 9 (SOX9) promotes CRC by activating a stem cell–like program that hinders intestinal differentiation. Intestinal adenomas and colorectal adenocarcinomas from mouse models and patients demonstrate ectopic and elevated expression of SOX9. Functional experiments indicate a requirement for SOX9 in human CRC cell lines and engineered neoplastic organoids. Disrupting SOX9 activity impairs primary CRC tumor growth by inducing intestinal differentiation. By binding to genome wide enhancers, SOX9 directly activates genes associated with Paneth and stem cell activity, including prominin 1 (PROM1). SOX9 up-regulates PROM1 via a Wnt-responsive intronic enhancer. A pentaspan transmembrane protein, PROM1 uses its first intracellular domain to support stem cell signaling, at least in part through SOX9, reinforcing a PROM1-SOX9 positive feedback loop. Conclusions: These studies establish SOX9 as a central regulator of an enhancer-driven stem cell–like program and carry important implications for developing therapeutics directed at overcoming differentiation defects in CRC. © 2022
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    Genomic Variant Annotation: A Comprehensive Review of Tools and Techniques
    (Springer Science and Business Media Deutschland GmbH, 2022) Hebbar, P.; Kamath S․, S.
    Variant annotation is the process by which variants and mutations in the DNA are assigned functional information and is a crucial process in genomic sequence analysis. The outcomes of such annotation are beneficial because they can directly influence the conclusions arrived at in disease studies. Once genomic sequencing data is processed, and variants are called, it is vital to recognise the functional content of this data and then analyse the data to prioritise these variants. This is an interesting problem in the computational biology field and presents many open challenges that are yet to be addressed. In this paper, a comprehensive review of current work addressing the problem of variant annotation is presented. We detail the various tools and methods that have been developed for variant annotation along with datasets that have been used by these methods. Insights on open challenges and directions for future research are also discussed. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.
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    The search for fast transients with CZTI
    (Springer, 2021) Sharma, Y.; Marathe, A.; Bhalerao, V.; Shenoy, V.; Waratkar, G.; Nadella, D.; Page, P.; Hebbar, P.; Vibhute, A.; Bhattacharya, D.; Rao, A.R.; Vadawale, S.
    The Cadmium–Zinc–Telluride Imager on AstroSat has proven to be a very effective All-Sky monitor in the hard X-ray regime, detecting over three hundred GRBs and putting highly competitive upper limits on X-ray emissions from gravitational wave sources and fast radio bursts. We present the algorithms used for searching for such transient sources in CZTI data, and for calculating upper limits in case of non-detections. We introduce CIFT: the CZTI Interface for Fast Transients, a framework used to streamline these processes. We present details of 87 new GRBs detected by this framework that were previously not detected in CZTI. © 2021, Indian Academy of Sciences.