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Das, Partha Pratim

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Das

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Partha Pratim

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Das, Partha Pratim

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2015 - 20173

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Author's Publications: search.filters.isAuthorOfPublication.5cb81b46-5478-4778-a30b-eb0c44e81acc

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    Variant-aware saturating mutagenesis using multiple Cas9 nucleases identifies regulatory elements at trait-associated loci
    (2017) Canver, Matthew C.; Lessard, Samuel; Pinello, Luca; Wu, Yuxuan; Ilboudo, Yann; Stern, Emily; Needleman, Austen; Galactéros, Frédéric; Brugnara, Carlo; Kutlar, Abdullah; McKenzie, Colin; Reid, Marvin; Chen, Diane D.; Das, Partha Pratim; Cole, Mitchel; Zeng, Jing; Kurita, Ryo; Nakamura, Yukio; Yuan, Guo-Cheng; Lettre, Guillaume; Bauer, Daniel; Orkin, Stuart
    Cas9-mediated, high-throughput, saturating in situ mutagenesis permits fine-mapping of function across genomic segments. Disease- and trait-associated variants from genome-wide association studies largely cluster in regulatory DNA. Here we demonstrate the use of multiple designer nucleases and variant-aware library design to interrogate trait-associated regulatory DNA at high resolution. We developed a computational tool for the creation of saturating mutagenesis libraries with single or combinatorial nucleases with incorporation of variants. We applied this methodology to the HBS1L-MYB intergenic region, a locus associated with red blood cell traits, including fetal hemoglobin levels. This approach identified putative regulatory elements that control MYB expression. Analysis of genomic copy number highlighted potential false positive regions, which emphasizes the importance of off-target analysis in design of saturating mutagenesis experiments. Taken together, these data establish a widely applicable high-throughput and high-resolution methodology to reliably identify minimal functional sequences within large regions of disease- and trait-associated DNA.
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    The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells
    (Springer Nature, 2016) Beyaz, Semir; Kim, Ji Hyung; Pinello, Luca; Xifaras, Michael E; Hu, Yu; Huang, Jialiang; Kerenyi, Marc A; Das, Partha Pratim; Barnitz, R Anthony; Herault, Aurelie; Dogum, Rizkullah; Haining, William; Yilmaz, Omer; Passegue, Emmanuelle; Yuan, Guo-Cheng; Orkin, Stuart; Winau, Florian
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    Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence
    (The Rockefeller University Press, 2015) Kim, Peter Geon; Nakano, Haruko; Das, Partha Pratim; Chen, Michael J.; Rowe, R. Grant; Chou, Stephanie S.; Ross, Samantha J.; Sakamoto, Kathleen M.; Zon, Leonard; Schlaeger, Thorsten; Orkin, Stuart; Nakano, Atsushi; Daley, George
    Fluid shear stress promotes the emergence of hematopoietic stem cells (HSCs) in the aorta–gonad–mesonephros (AGM) of the developing mouse embryo. We determined that the AGM is enriched for expression of targets of protein kinase A (PKA)–cAMP response element-binding protein (CREB), a pathway activated by fluid shear stress. By analyzing CREB genomic occupancy from chromatin-immunoprecipitation sequencing (ChIP-seq) data, we identified the bone morphogenetic protein (BMP) pathway as a potential regulator of CREB. By chemical modulation of the PKA–CREB and BMP pathways in isolated AGM VE-cadherin+ cells from mid-gestation embryos, we demonstrate that PKA–CREB regulates hematopoietic engraftment and clonogenicity of hematopoietic progenitors, and is dependent on secreted BMP ligands through the type I BMP receptor. Finally, we observed blunting of this signaling axis using Ncx1-null embryos, which lack a heartbeat and intravascular flow. Collectively, we have identified a novel PKA–CREB–BMP signaling pathway downstream of shear stress that regulates HSC emergence in the AGM via the endothelial-to-hematopoietic transition.