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146 results on '"Weiss, Mitchell J."'

1. Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells

Author

Lian, Xizhen, Chatterjee, Sumanta, Sun, Yehui, Dilliard, Sean A., Moore, Stephen, Xiao, Yufen, Bian, Xiaoyan, Yamada, Kohki, Sung, Yun-Chieh, Levine, Rachel M., Mayberry, Kalin, John, Samuel, Liu, Xiaoye, Smith, Caroline, Johnson, Lindsay T., Wang, Xu, Zhang, Cheng Cheng, Liu, David R., Newby, Gregory A., Weiss, Mitchell J., Yen, Jonathan S., and Siegwart, Daniel J.

Published
2024
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2. Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+ cell therapy to induce fetal hemoglobin for sickle cell disease

Author

Katta, Varun, O’Keefe, Kiera, Li, Yichao, Mayuranathan, Thiyagaraj, Lazzarotto, Cicera R., Wood, Rachael K., Levine, Rachel M., Powers, Alicia, Mayberry, Kalin, Manquen, Garret, Yao, Yu, Zhang, Jingjing, Jang, Yoonjeong, Nimmagadda, Nikitha, Dempsey, Erin A., Lee, GaHyun, Uchida, Naoya, Cheng, Yong, Fazio, Frank, Lockey, Tim, Meagher, Mike, Sharma, Akshay, Tisdale, John F., Zhou, Sheng, Yen, Jonathan S., Weiss, Mitchell J., and Tsai, Shengdar Q.

Published
2024
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5. Potent and uniform fetal hemoglobin induction via base editing

Author

Mayuranathan, Thiyagaraj, Newby, Gregory A., Feng, Ruopeng, Yao, Yu, Mayberry, Kalin D., Lazzarotto, Cicera R., Li, Yichao, Levine, Rachel M., Nimmagadda, Nikitha, Dempsey, Erin, Kang, Guolian, Porter, Shaina N., Doerfler, Phillip A., Zhang, Jingjing, Jang, Yoonjeong, Chen, Jingjing, Bell, Henry W., Crossley, Merlin, Bhoopalan, Senthil Velan, Sharma, Akshay, Tisdale, John F., Pruett-Miller, Shondra M., Cheng, Yong, Tsai, Shengdar Q., Liu, David R., Weiss, Mitchell J., and Yen, Jonathan S.

Published
2023
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8. Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice

Author

Everette, Kelcee A., Newby, Gregory A., Levine, Rachel M., Mayberry, Kalin, Jang, Yoonjeong, Mayuranathan, Thiyagaraj, Nimmagadda, Nikitha, Dempsey, Erin, Li, Yichao, Bhoopalan, Senthil Velan, Liu, Xiong, Davis, Jessie R., Nelson, Andrew T., Chen, Peter J., Sousa, Alexander A., Cheng, Yong, Tisdale, John F., Weiss, Mitchell J., Yen, Jonathan S., and Liu, David R.

Published
2023
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9. ETV6 represses inflammatory response genes and regulates HSPC function during stress hematopoiesis in mice

Author

Bloom, Mackenzie, Oak, Ninad, Baskin-Doerfler, Rebekah, Feng, Ruopeng, Iacobucci, Ilaria, Baviskar, Pradyumna, Zhao, Xujie, Stroh, Alexa N., Li, Chunliang, Ozark, Patrick, Tillman, Heather S., Li, Yichao, Verbist, Katherine C., Albeituni, Sabrin, Scott, Danny C., King, Moeko T., McKinney-Freeman, Shannon L., Weiss, Mitchell J., Yang, Jun J., and Nichols, Kim E.

Published
2023
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14. Endothelial alpha globin is a nitrite reductase

Author

Keller, IV, T. C. Stevenson, Lechauve, Christophe, Keller, Alexander S., Broseghini-Filho, Gilson Brás, Butcher, Joshua T., Askew Page, Henry R., Islam, Aditi, Tan, Zhe Yin, DeLalio, Leon J., Brooks, Steven, Sharma, Poonam, Hong, Kwangseok, Xu, Wenhao, Padilha, Alessandra Simão, Ruddiman, Claire A., Best, Angela K., Macal, Edgar, Kim-Shapiro, Daniel B., Christ, George, Yan, Zhen, Cortese-Krott, Miriam M., Ricart, Karina, Patel, Rakesh, Bender, Timothy P., Sonkusare, Swapnil K., Weiss, Mitchell J., Ackerman, Hans, Columbus, Linda, and Isakson, Brant E.

Published
2022
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16. Ancestral β-globin gene haplotypes modify β-thalassemia severity in a mouse model

Author

Lechauve, Christophe, primary, Keith, Julia, additional, Fernandez, Alfonso G., additional, Khandros, Eugene, additional, Mayberry, Kalin, additional, Mayuranathan, Thiyagaraj, additional, Palmer, Lance E, additional, Qiu, Xiaohui, additional, Sheppard, Heather, additional, Telange, Rahul, additional, Herz, Hans-Martin, additional, and Weiss, Mitchell J., additional

Published
2024
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17. Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+cell therapy to induce fetal hemoglobin for sickle cell disease

Author

Katta, Varun, O’Keefe, Kiera, Li, Yichao, Mayuranathan, Thiyagaraj, Lazzarotto, Cicera R., Wood, Rachael K., Levine, Rachel M., Powers, Alicia, Mayberry, Kalin, Manquen, Garret, Yao, Yu, Zhang, Jingjing, Jang, Yoonjeong, Nimmagadda, Nikitha, Dempsey, Erin A., Lee, GaHyun, Uchida, Naoya, Cheng, Yong, Fazio, Frank, Lockey, Tim, Meagher, Mike, Sharma, Akshay, Tisdale, John F., Zhou, Sheng, Yen, Jonathan S., Weiss, Mitchell J., and Tsai, Shengdar Q.

Abstract

Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although the FDA released guidelines for evaluating genome editing risks, it remains unclear how best to approach pre-clinical assessment of genome-edited cell products. Here, we describe rigorous pre-clinical development of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug application cleared by the FDA. We compared γ-globin promoter and BCL11Aenhancer targets, identified a potent HbF-inducing lead candidate, and tested our approach in mobilized CD34+hematopoietic stem progenitor cells (HSPCs) from SCD patients. We observed efficient editing, HbF induction to predicted therapeutic levels, and reduced sickling. With single-cell analyses, we defined the heterogeneity of HbF induction and HBG1/HBG2transcription. With CHANGE-seq for sensitive and unbiased off-target discovery followed by targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new ex vivoHSC genome editing strategies toward clinical trials for treating SCD and other blood disorders.

Published
2024
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19. Cross-species regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes

Author

Xiang, Guanjue, primary, He, Xi, additional, Giardine, Belinda M., additional, Weaver, Kathryn J., additional, Taylor, Dylan J., additional, McCoy, Rajiv C., additional, Jansen, Camden, additional, Keller, Cheryl A., additional, Wixom, Alexander Q., additional, Cockburn, April, additional, Miller, Amber, additional, Qi, Qian, additional, He, Yanghua, additional, Li, Yichao, additional, Lichtenberg, Jens, additional, Heuston, Elisabeth F., additional, Anderson, Stacie M., additional, Luan, Jing, additional, Vermunt, Marit W., additional, Yue, Feng, additional, Sauria, Michael E.G., additional, Schatz, Michael C., additional, Taylor, James, additional, Göttgens, Berthold, additional, Hughes, Jim R., additional, Higgs, Douglas R., additional, Weiss, Mitchell J., additional, Cheng, Yong, additional, Blobel, Gerd A., additional, Bodine, David, additional, Zhang, Yu, additional, Li, Qunhua, additional, Mahony, Shaun, additional, and Hardison, Ross C., additional

Published
2023
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20. Data from St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem

Author

McLeod, Clay, primary, Gout, Alexander M., primary, Zhou, Xin, primary, Thrasher, Andrew, primary, Rahbarinia, Delaram, primary, Brady, Samuel W., primary, Macias, Michael, primary, Birch, Kirby, primary, Finkelstein, David, primary, Sunny, Jobin, primary, Mudunuri, Rahul, primary, Orr, Brent A., primary, Treadway, Madison, primary, Davidson, Bob, primary, Ard, Tracy K., primary, Chiao, Arthur, primary, Swistak, Andrew, primary, Wiggins, Stephanie, primary, Foy, Scott, primary, Wang, Jian, primary, Sioson, Edgar, primary, Wang, Shuoguo, primary, Michael, J. Robert, primary, Liu, Yu, primary, Ma, Xiaotu, primary, Patel, Aman, primary, Edmonson, Michael N., primary, Wilkinson, Mark R., primary, Frantz, Andrew M., primary, Chang, Ti-Cheng, primary, Tian, Liqing, primary, Lei, Shaohua, primary, Islam, S.M. Ashiqul, primary, Meyer, Christopher, primary, Thangaraj, Naina, primary, Tater, Pamella, primary, Kandali, Vijay, primary, Ma, Singer, primary, Nguyen, Tuan, primary, Serang, Omar, primary, McGuire, Irina, primary, Robison, Nedra, primary, Gentry, Darrell, primary, Tang, Xing, primary, Palmer, Lance E., primary, Wu, Gang, primary, Suh, Ed, primary, Tanner, Leigh, primary, McMurry, James, primary, Lear, Matthew, primary, Pappo, Alberto S., primary, Wang, Zhaoming, primary, Wilson, Carmen L., primary, Cheng, Yong, primary, Meshinchi, Soheil, primary, Alexandrov, Ludmil B., primary, Weiss, Mitchell J., primary, Armstrong, Gregory T., primary, Robison, Leslie L., primary, Yasui, Yutaka, primary, Nichols, Kim E., primary, Ellison, David W., primary, Bangur, Chaitanya, primary, Mullighan, Charles G., primary, Baker, Suzanne J., primary, Dyer, Michael A., primary, Miller, Geralyn, primary, Newman, Scott, primary, Rusch, Michael, primary, Daly, Richard, primary, Perry, Keith, primary, Downing, James R., primary, and Zhang, Jinghui, primary

Published
2023
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21. Supplementary Tables from St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem

Author

McLeod, Clay, primary, Gout, Alexander M., primary, Zhou, Xin, primary, Thrasher, Andrew, primary, Rahbarinia, Delaram, primary, Brady, Samuel W., primary, Macias, Michael, primary, Birch, Kirby, primary, Finkelstein, David, primary, Sunny, Jobin, primary, Mudunuri, Rahul, primary, Orr, Brent A., primary, Treadway, Madison, primary, Davidson, Bob, primary, Ard, Tracy K., primary, Chiao, Arthur, primary, Swistak, Andrew, primary, Wiggins, Stephanie, primary, Foy, Scott, primary, Wang, Jian, primary, Sioson, Edgar, primary, Wang, Shuoguo, primary, Michael, J. Robert, primary, Liu, Yu, primary, Ma, Xiaotu, primary, Patel, Aman, primary, Edmonson, Michael N., primary, Wilkinson, Mark R., primary, Frantz, Andrew M., primary, Chang, Ti-Cheng, primary, Tian, Liqing, primary, Lei, Shaohua, primary, Islam, S.M. Ashiqul, primary, Meyer, Christopher, primary, Thangaraj, Naina, primary, Tater, Pamella, primary, Kandali, Vijay, primary, Ma, Singer, primary, Nguyen, Tuan, primary, Serang, Omar, primary, McGuire, Irina, primary, Robison, Nedra, primary, Gentry, Darrell, primary, Tang, Xing, primary, Palmer, Lance E., primary, Wu, Gang, primary, Suh, Ed, primary, Tanner, Leigh, primary, McMurry, James, primary, Lear, Matthew, primary, Pappo, Alberto S., primary, Wang, Zhaoming, primary, Wilson, Carmen L., primary, Cheng, Yong, primary, Meshinchi, Soheil, primary, Alexandrov, Ludmil B., primary, Weiss, Mitchell J., primary, Armstrong, Gregory T., primary, Robison, Leslie L., primary, Yasui, Yutaka, primary, Nichols, Kim E., primary, Ellison, David W., primary, Bangur, Chaitanya, primary, Mullighan, Charles G., primary, Baker, Suzanne J., primary, Dyer, Michael A., primary, Miller, Geralyn, primary, Newman, Scott, primary, Rusch, Michael, primary, Daly, Richard, primary, Perry, Keith, primary, Downing, James R., primary, and Zhang, Jinghui, primary

Published
2023
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22. Supplementary Data from St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem

Author

McLeod, Clay, primary, Gout, Alexander M., primary, Zhou, Xin, primary, Thrasher, Andrew, primary, Rahbarinia, Delaram, primary, Brady, Samuel W., primary, Macias, Michael, primary, Birch, Kirby, primary, Finkelstein, David, primary, Sunny, Jobin, primary, Mudunuri, Rahul, primary, Orr, Brent A., primary, Treadway, Madison, primary, Davidson, Bob, primary, Ard, Tracy K., primary, Chiao, Arthur, primary, Swistak, Andrew, primary, Wiggins, Stephanie, primary, Foy, Scott, primary, Wang, Jian, primary, Sioson, Edgar, primary, Wang, Shuoguo, primary, Michael, J. Robert, primary, Liu, Yu, primary, Ma, Xiaotu, primary, Patel, Aman, primary, Edmonson, Michael N., primary, Wilkinson, Mark R., primary, Frantz, Andrew M., primary, Chang, Ti-Cheng, primary, Tian, Liqing, primary, Lei, Shaohua, primary, Islam, S.M. Ashiqul, primary, Meyer, Christopher, primary, Thangaraj, Naina, primary, Tater, Pamella, primary, Kandali, Vijay, primary, Ma, Singer, primary, Nguyen, Tuan, primary, Serang, Omar, primary, McGuire, Irina, primary, Robison, Nedra, primary, Gentry, Darrell, primary, Tang, Xing, primary, Palmer, Lance E., primary, Wu, Gang, primary, Suh, Ed, primary, Tanner, Leigh, primary, McMurry, James, primary, Lear, Matthew, primary, Pappo, Alberto S., primary, Wang, Zhaoming, primary, Wilson, Carmen L., primary, Cheng, Yong, primary, Meshinchi, Soheil, primary, Alexandrov, Ludmil B., primary, Weiss, Mitchell J., primary, Armstrong, Gregory T., primary, Robison, Leslie L., primary, Yasui, Yutaka, primary, Nichols, Kim E., primary, Ellison, David W., primary, Bangur, Chaitanya, primary, Mullighan, Charles G., primary, Baker, Suzanne J., primary, Dyer, Michael A., primary, Miller, Geralyn, primary, Newman, Scott, primary, Rusch, Michael, primary, Daly, Richard, primary, Perry, Keith, primary, Downing, James R., primary, and Zhang, Jinghui, primary

Published
2023
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24. Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome

Author

Leiding, Jennifer W., primary, Vogel, Tiphanie P., additional, Santarlas, Valentine G.J., additional, Mhaskar, Rahul, additional, Smith, Madison R., additional, Carisey, Alexandre, additional, Vargas-Hernández, Alexander, additional, Silva-Carmona, Manuel, additional, Heeg, Maximilian, additional, Rensing-Ehl, Anne, additional, Neven, Bénédicte, additional, Hadjadj, Jérôme, additional, Hambleton, Sophie, additional, Ronan Leahy, Timothy, additional, Meesilpavikai, Kornvalee, additional, Cunningham-Rundles, Charlotte, additional, Dutmer, Cullen M., additional, Sharapova, Svetlana O., additional, Taskinen, Mervi, additional, Chua, Ignatius, additional, Hague, Rosie, additional, Klemann, Christian, additional, Kostyuchenko, Larysa, additional, Morio, Tomohiro, additional, Thatayatikom, Akaluck, additional, Ozen, Ahmet, additional, Scherbina, Anna, additional, Bauer, Cindy S., additional, Flanagan, Sarah E., additional, Gambineri, Eleonora, additional, Giovannini-Chami, Lisa, additional, Heimall, Jennifer, additional, Sullivan, Kathleen E., additional, Allenspach, Eric, additional, Romberg, Neil, additional, Deane, Sean G., additional, Prince, Benjamin T., additional, Rose, Melissa J., additional, Bohnsack, John, additional, Mousallem, Talal, additional, Jesudas, Rohith, additional, Santos Vilela, Maria Marluce Dos, additional, O’Sullivan, Michael, additional, Pachlopnik Schmid, Jana, additional, Průhová, Štěpánka, additional, Klocperk, Adam, additional, Rees, Matthew, additional, Su, Helen, additional, Bahna, Sami, additional, Baris, Safa, additional, Bartnikas, Lisa M., additional, Chang Berger, Amy, additional, Briggs, Tracy A., additional, Brothers, Shannon, additional, Bundy, Vanessa, additional, Chan, Alice Y., additional, Chandrakasan, Shanmuganathan, additional, Christiansen, Mette, additional, Cole, Theresa, additional, Cook, Matthew C., additional, Desai, Mukesh M., additional, Fischer, Ute, additional, Fulcher, David A., additional, Gallo, Silvanna, additional, Gauthier, Amelie, additional, Gennery, Andrew R., additional, Gonçalo Marques, José, additional, Gottrand, Frédéric, additional, Grimbacher, Bodo, additional, Grunebaum, Eyal, additional, Haapaniemi, Emma, additional, Hämäläinen, Sari, additional, Heiskanen, Kaarina, additional, Heiskanen-Kosma, Tarja, additional, Hoffman, Hal M., additional, Gonzalez-Granado, Luis Ignacio, additional, Guerrerio, Anthony L., additional, Kainulainen, Leena, additional, Kumar, Ashish, additional, Lawrence, Monica G., additional, Levin, Carina, additional, Martelius, Timi, additional, Neth, Olaf, additional, Olbrich, Peter, additional, Palma, Alejandro, additional, Patel, Niraj C., additional, Pozos, Tamara, additional, Preece, Kahn, additional, Lugo Reyes, Saúl Oswaldo, additional, Russell, Mark A., additional, Schejter, Yael, additional, Seroogy, Christine, additional, Sinclair, Jan, additional, Skevofilax, Effie, additional, Suan, Daniel, additional, Suez, Daniel, additional, Szabolcs, Paul, additional, Velasco, Helena, additional, Warnatz, Klaus, additional, Walkovich, Kelly, additional, Worth, Austen, additional, Seppänen, Mikko R.J., additional, Torgerson, Troy R., additional, Sogkas, Georgios, additional, Ehl, Stephan, additional, Tangye, Stuart G., additional, Cooper, Megan A., additional, Milner, Joshua D., additional, Forbes Satter, Lisa R., additional, Aleshkevich, Svetlana, additional, Allende, Luis M., additional, Atkinson, T. Prescott, additional, Atschekzei, Faranaz, additional, Aydemir, Sezin, additional, Aygunes, Utku, additional, Barlogis, Vincent, additional, Baumann, Ulrich, additional, Belko, John, additional, Bezrodnik, Liliana, additional, Biebl, Ariane, additional, Broderick, Lori, additional, Bunin, Nancy J., additional, Caldirola, Maria Soledad, additional, Castelle, Martin, additional, Celmeli, Fatih, additional, Charbonnier, Louis-Marie, additional, Chatila, Talal A., additional, Chellapandian, Deepak, additional, Cokugras, Haluk, additional, Conlon, Niall, additional, Cox, Fionnuala, additional, Crickx, Etienne, additional, Dalgic, Buket, additional, ASH Dalm, Virgil, additional, Danielian, Silvia, additional, Dominguez-Pinilla, Nerea, additional, Dujovny, Tal, additional, Ebbo, Mikael, additional, Eken, Ahmet, additional, Esty, Brittany, additional, Fabre, Alexandre, additional, Fischer, Alain, additional, Hannibal, Mark, additional, Huppert, Laura, additional, Ikeda, Marc D., additional, Jolles, Stephen, additional, Jolly, Kent W., additional, Jones, Neil, additional, Kanariou, Maria, additional, Karakoc-Aydiner, Elif, additional, Karamantziani, Theoni, additional, Kelaidi, Charikleia, additional, Keogan, Mary, additional, Pac Kisaarslan, Ayşenur, additional, Kiykim, Ayca, additional, Kotsonis, Kosmas, additional, Kuzmenko, Natalia, additional, Leroy, Sylvie, additional, Lianou, Dimitra, additional, Longhurst, Hilary, additional, Lorenz, Myriam Ricarda, additional, Maffucci, Patrick, additional, Manson, Ania, additional, Marchal, Sarah, additional, Malphettes, Marion, additional, Marega, Lia Furlaneto, additional, Mauracher, Andrea A., additional, Miller, Holly, additional, Mombourquette, Joy, additional, Morgan, Noel G., additional, Mukhina, Anna, additional, Nathalie, Aladjidi, additional, Nelken, Brigitte, additional, Nolan, David, additional, Norlin, Anna-Carin, additional, Oleastro, Matias, additional, Ozcan, Alper, additional, Pasquet, Marlene, additional, Pegler, José Roberto, additional, Picard, Capucine, additional, Polychronopoulou, Sophia, additional, Quartier, Pierre, additional, Quesada, Juan Francisco, additional, Ramakers, Jan, additional, Randall, Katrina L., additional, Rao, V. Koneti, additional, Remiker, Allison, additional, Resin, Geraldine, additional, Richmond, Peter, additional, Rieux-Laucat, Frederic, additional, Rodina, Yulia, additional, Rohrlich, Pierre, additional, Sachs, Johnathan, additional, Sakovich, Inga, additional, Santarlas, Christopher, additional, Sari, Sinan, additional, Sawicki, Gregory, additional, Schauer, Uwe, additional, Scheffler Mendoza, Selma C., additional, Schvetz, Oksana, additional, Schmidt, Reinhold Ernst, additional, Schwarz, Klaus, additional, Sediva, Anna, additional, Sinclair, Kyle, additional, Slatter, Mary, additional, Sleasman, John, additional, Stergiou, Katerina, additional, Suratannon, Narissara, additional, Tanita, Kay, additional, Thompson, Grace, additional, Travis, Stephen, additional, Trojan, Timothy, additional, Tsinti, Maria, additional, Unal, Ekrem, additional, Urdinez, Luciano, additional, Vazquez-Gomez, Felisa, additional, Villa, Mariana, additional, Weinrich, Michael, additional, Weiss, Mitchell J., additional, Wright, Benjamin, additional, Yilmaz, Ebru, additional, Zachova, Radana, additional, and Zhang, Yu, additional

Published
2023
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25. Genetic regulation of fetal hemoglobin across global populations

Author

Cato, Liam D, Li, Rick, Lu, Henry Y, Yu, Fulong, Wissman, Mariel, Mkumbe, Baraka S, Ekwattanakit, Supachai, Deelen, Patrick, Mwita, Liberata, Sangeda, Raphael Zozimus, Suksangpleng, Thidarat, Riolueang, Suchada, Bronson, Paola G, Paul, Dirk S, Kawabata, Emily, Astle, William J, Aguet, Francois, Ardlie, Kristin, Lopez de Lapuente Portilla, Aitzkoa, Kang, Guolian, Zhang, Yingze, Nouraie, Seyed Mehdi, Gordeuk, Victor R, Gladwin, Mark T, Garrett, Melanie E, Ashley-Koch, Allison, Telen, Marilyn J, Custer, Brian, Kelly, Shannon, DINARDO, CARLA, Sabino, Ester Cerdeira, Loureiro, Paula, Carneiro-Proietti, Anna Barbara, Maximo, Claudia, Mendez, Adriana, Hammerer-Lercher, Angelika, Sheehan, Vivien A, Weiss, Mitchell J, Franke, Lude, Nilsson, Bjorn, Butterworth, Adam S, Viprakasit, Vip, Nkya, Siana, and Sankaran, Vijay G.

Subjects
Article
Abstract

Human genetic variation has enabled the identification of several key regulators of fetal-to-adult hemoglobin switching, including BCL11A, resulting in therapeutic advances. However, despite the progress made, limited further insights have been obtained to provide a fuller accounting of how genetic variation contributes to the global mechanisms of fetal hemoglobin (HbF) gene regulation. Here, we have conducted a multi-ancestry genome-wide association study of 28,279 individuals from several cohorts spanning 5 continents to define the architecture of human genetic variation impacting HbF. We have identified a total of 178 conditionally independent genome-wide significant or suggestive variants across 14 genomic windows. Importantly, these new data enable us to better define the mechanisms by which HbF switching occurs in vivo. We conduct targeted perturbations to define BACH2 as a new genetically-nominated regulator of hemoglobin switching. We define putative causal variants and underlying mechanisms at the well-studied BCL11A and HBS1L-MYB loci, illuminating the complex variant-driven regulation present at these loci. We additionally show how rare large-effect deletions in the HBB locus can interact with polygenic variation to influence HbF levels. Our study paves the way for the next generation of therapies to more effectively induce HbF in sickle cell disease and β-thalassemia.

Published
2023

26. Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes

Author

Xiang, Guanjue, He, Xi, Giardine, Belinda M., Isaac, Kathryn J., Taylor, Dylan J., McCoy, Rajiv C., Jansen, Camden, Keller, Cheryl A., Wixom, Alexander Q., Cockburn, April, Miller, Amber, Qi, Qian, He, Yanghua, Li, Yichao, Lichtenberg, Jens, Heuston, Elisabeth F., Anderson, Stacie M., Luan, Jing, Vermunt, Marit W., Yue, Feng, Sauria, Michael E.G., Schatz, Michael C., Taylor, James, Go¨ttgens, Berthold, Hughes, Jim R., Higgs, Douglas R., Weiss, Mitchell J., Cheng, Yong, Blobel, Gerd A., Bodine, David M., Zhang, Yu, Li, Qunhua, Mahony, Shaun, and Hardison, Ross C.

Abstract

Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state regulatory potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbor distinctive transcription factor binding motifs that are similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we show that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

Published
2024
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27. Multiplex Base Editing to Protect from CD33-Directed Therapy: Implications for Immune and Gene Therapy

Author

Borot, Florence, primary, Humbert, Olivier, additional, Newby, Gregory A, additional, Fields, Emily, additional, Kohli, Sajeev, additional, Radtke, Stefan, additional, Laszlo, George S., additional, Mayuranathan, Thiyagaraj, additional, Ali, Abdullah Mahmood, additional, Weiss, Mitchell J., additional, Yen, Jonathan S., additional, Walter, Roland B., additional, Liu, David R., additional, Mukherjee, Siddhartha, additional, and Kiem, Hans-Peter, additional

Published
2023
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28. An RPS19-edited model for Diamond-Blackfan anemia reveals TP53-dependent impairment of hematopoietic stem cell activity

Author

Bhoopalan, Senthil Velan, primary, Yen, Jonathan S., additional, Mayuranathan, Thiyagaraj, additional, Mayberry, Kalin D., additional, Yao, Yu, additional, Lillo Osuna, Maria Angeles, additional, Jang, Yoonjeong, additional, Liyanage, Janaka S.S., additional, Blanc, Lionel, additional, Ellis, Steven R., additional, Wlodarski, Marcin W., additional, and Weiss, Mitchell J., additional

Published
2023
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29. Forced enhancer-promoter rewiring to alter gene expression in animal models

Author

Peslak, Scott A., primary, Demirci, Selami, additional, Chandra, Vemika, additional, Ryu, Byoung, additional, Bhardwaj, Saurabh K., additional, Jiang, Jing, additional, Rupon, Jeremy W., additional, Throm, Robert E., additional, Uchida, Naoya, additional, Leonard, Alexis, additional, Essawi, Khaled, additional, Bonifacino, Aylin C., additional, Krouse, Allen E., additional, Linde, Nathaniel S., additional, Donahue, Robert E., additional, Ferrara, Francesca, additional, Wielgosz, Matthew, additional, Abdulmalik, Osheiza, additional, Hamagami, Nicole, additional, Germino-Watnick, Paula, additional, Le, Anh, additional, Chu, Rebecca, additional, Hinds, Malikiya, additional, Weiss, Mitchell J., additional, Tong, Wei, additional, Tisdale, John F., additional, and Blobel, Gerd A., additional

Published
2023
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30. Modular UBE2H-CTLH E2-E3 complexes regulate erythroid maturation

Author

Sherpa, Dawafuti, primary, Mueller, Judith, primary, Karayel, Özge, primary, Xu, Peng, primary, Yao, Yu, additional, Chrustowicz, Jakub, additional, Gottemukkala, Karthik V, additional, Baumann, Christine, additional, Gross, Annette, additional, Czarnecki, Oliver, additional, Zhang, Wei, additional, Gu, Jun, additional, Nilvebrant, Johan, additional, Sidhu, Sachdev S, additional, Murray, Peter J, additional, Mann, Matthias, additional, Weiss, Mitchell J, additional, Schulman, Brenda A, additional, and Alpi, Arno F, additional

Published
2022
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32. Increased Potency and Uniformity of Fetal Hemoglobin Induction from Base Editing Compared to Cas9 Nuclease

Author

Mayuranathan, Thiyagaraj, primary, Newby, Gregory A., additional, Feng, Ruopeng, additional, Yao, Yu, additional, Mayberry, Kalin, additional, Kang, Guolian, additional, Lazzarotto, Cicera, additional, Li, Yichao, additional, Levine, Rachel, additional, Dempsey, Erin, additional, Porter, Shaina N., additional, Doerfler, Phillip A, additional, Zhang, Jingjing, additional, Jang, Yoonjeong, additional, Bhoopalan, Senthil, additional, Nimmagadda, Nikitha, additional, Sharma, Akshay, additional, Tisdale, John, additional, Miller, Shondra, additional, Cheng, Yong, additional, Tsai, Shengdar, additional, Weiss, Mitchell J., additional, Liu, David R., additional, and Yen, Jonathan S, additional

Published
2022
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33. Base Editing for Therapeutic Induction of Fetal Hemoglobin in β-Thalassemia

Author

Christakopoulos, Georgios E., primary, Mayuranathan, Thiyagaraj, additional, Fernandez, Alfonso G., additional, Mayberry, Kalin, additional, Yao, Yu, additional, Telange, Rahul, additional, Dudley, Michael, additional, Levine, Rachel, additional, Dempsey, Erin, additional, Liu, David R., additional, Yen, Jonathan S, additional, and Weiss, Mitchell J., additional

Published
2022
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34. ETV6 Represses TNF during Stress Hematopoiesis and Regulates HSC Self Renewal

Author

Bloom, Mackenzie, primary, Baskin-Doerfler, Rebekah, additional, Oak, Ninad, additional, Feng, Ruopeng, additional, Zhao, Xujie, additional, Li, Chunliang, additional, Ozark, Patrick, additional, Verbist, Katherine, additional, Stroh, Alexa, additional, Albeituni, Sabrin, additional, Maise, JaQuel, additional, Weiss, Mitchell J., additional, McKinney-Freeman, Shannon, additional, Yang, Jun J.J., additional, and Nichols, Kim E., additional

Published
2022
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35. Author response: Modular UBE2H-CTLH E2-E3 complexes regulate erythroid maturation

Author

Sherpa, Dawafuti, primary, Mueller, Judith, primary, Karayel, Özge, primary, Xu, Peng, primary, Yao, Yu, additional, Chrustowicz, Jakub, additional, Gottemukkala, Karthik V, additional, Baumann, Christine, additional, Gross, Annette, additional, Czarnecki, Oliver, additional, Zhang, Wei, additional, Gu, Jun, additional, Nilvebrant, Johan, additional, Sidhu, Sachdev S, additional, Murray, Peter J, additional, Mann, Matthias, additional, Weiss, Mitchell J, additional, Schulman, Brenda A, additional, and Alpi, Arno F, additional

Published
2022
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38. Optimizing haematopoietic stem and progenitor cell apheresis collection from plerixafor‐mobilized patients with sickle cell disease

Author

Sharma, Akshay, primary, Leonard, Alexis, additional, West, Kamille, additional, Gossett, Jeffrey M., additional, Uchida, Naoya, additional, Panch, Sandhya, additional, Stroncek, David, additional, Poston, Leigh, additional, Akel, Salem, additional, Hankins, Jane S., additional, Fitzhugh, Courtney, additional, Hsieh, Matthew M., additional, Kang, Guolian, additional, Tisdale, John F., additional, Weiss, Mitchell J., additional, and Zheng, Yan, additional

Published
2022
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40. Modular UBE2H-CTLH E2-E3 complexes regulate erythroid maturation

Author

Sherpa, Dawafuti, Mueller, Judith, Karayel, Oezge, Xu, Peng, Yao, Yu, Chrustowicz, Jakub, Gottemukkala, Karthik, V, Baumann, Christine, Gross, Annette, Czarnecki, Oliver, Zhang, Wei, Gu, Jun, Nilvebrant, Johan, Sidhu, Sachdev S., Murray, Peter J., Mann, Matthias, Weiss, Mitchell J., Schulman, Brenda A., Alpi, Arno F., Sherpa, Dawafuti, Mueller, Judith, Karayel, Oezge, Xu, Peng, Yao, Yu, Chrustowicz, Jakub, Gottemukkala, Karthik, V, Baumann, Christine, Gross, Annette, Czarnecki, Oliver, Zhang, Wei, Gu, Jun, Nilvebrant, Johan, Sidhu, Sachdev S., Murray, Peter J., Mann, Matthias, Weiss, Mitchell J., Schulman, Brenda A., and Alpi, Arno F.

Abstract

The development of haematopoietic stem cells into mature erythrocytes - erythropoiesis - is a controlled process characterized by cellular reorganization and drastic reshaping of the proteome landscape. Failure of ordered erythropoiesis is associated with anaemias and haematological malignancies. Although the ubiquitin system is a known crucial post-translational regulator in erythropoiesis, how the erythrocyte is reshaped by the ubiquitin system is poorly understood. By measuring the proteomic landscape of in vitro human erythropoiesis models, we found dynamic differential expression of subunits of the CTLH E3 ubiquitin ligase complex that formed maturation stage-dependent assemblies of topologically homologous RANBP9- and RANBP10-CTLH complexes. Moreover, protein abundance of CTLH's cognate E2 ubiquitin conjugating enzyme UBE2H increased during terminal differentiation, and UBE2H expression depended on catalytically active CTLH E3 complexes. CRISPR-Cas9-mediated inactivation of CTLH E3 assemblies or UBE2H in erythroid progenitors revealed defects, including spontaneous and accelerated erythroid maturation as well as inefficient enucleation. Thus, we propose that dynamic maturation stage-specific changes of UBE2H-CTLH E2-E3 modules control the orderly progression of human erythropoiesis., QC 20221223

Published
2022
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41. The role of globins in cardiovascular physiology

Author

Keller, T. C. Stevenson, primary, Lechauve, Christophe, additional, Keller, Alexander S., additional, Brooks, Steven, additional, Weiss, Mitchell J., additional, Columbus, Linda, additional, Ackerman, Hans, additional, Cortese-Krott, Miriam M., additional, and Isakson, Brant E., additional

Published
2022
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42. Differential UBE2H-CTLH E2-E3 ubiquitylation modules regulate erythroid maturation

Author

Sherpa, Dawafuti, primary, Müller, Judith, additional, Karayel, Özge, additional, Chrustowicz, Jakub, additional, Xu, Peng, additional, Gottemukkala, Karthik V., additional, Baumann, Christine, additional, Gross, Annette, additional, Czarnezki, Oliver, additional, Zhang, Wei, additional, Gu, Jun, additional, Nilvebrant, Johan, additional, Weiss, Mitchell J., additional, Sidhu, Sachdev S., additional, Murray, Peter J., additional, Mann, Matthias, additional, Schulman, Brenda A., additional, and Alpi, Arno F., additional

Published
2022
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43. Redox-Regulation of α-Globin in Vascular Physiology

Author

Kiger, Laurent, primary, Keith, Julia, additional, Freiwan, Abdullah, additional, Fernandez, Alfonso G., additional, Tillman, Heather, additional, Isakson, Brant E., additional, Weiss, Mitchell J., additional, and Lechauve, Christophe, additional

Published
2022
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44. SCP4-STK35/PDIK1L complex is a dual phospho-catalytic signaling dependency in acute myeloid leukemia

Author

Polyanskaya, Sofya A., primary, Moreno, Rosamaria Y., additional, Lu, Bin, additional, Feng, Ruopeng, additional, Yao, Yu, additional, Irani, Seema, additional, Klingbeil, Olaf, additional, Yang, Zhaolin, additional, Wei, Yiliang, additional, Demerdash, Osama E., additional, Benjamin, Lukas A., additional, Weiss, Mitchell J., additional, Zhang, Yan Jessie, additional, and Vakoc, Christopher R., additional

Published
2022
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45. Regulation of Fetal Hemoglobin Expression By the VHL-HIF1α Oxygen Sensing System

Author

Feng, Ruopeng, primary, Mayuranathan, Thiyagaraj, additional, Huang, Peng, additional, Doerfler, Phillip A, additional, Li, Yichao, additional, Yao, Yu, additional, Zhang, Jingjing, additional, Palmer, Lance E., additional, Xu, Peng, additional, Mayberry, Kalin, additional, Wright, Shaela, additional, Li, Chunliang, additional, Cheng, Yong, additional, Blobel, Gerd A., additional, Simon, M. Celeste, additional, and Weiss, Mitchell J., additional

Published
2021
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46. Optimization of Autologous Hematopoietic Progenitor Stem Cell Apheresis Collection from Plerixafor-Mobilized Patients with Sickle Cell Disease

Author

Zheng, Yan, primary, Sharma, Akshay, additional, Leonard, Alexis, additional, West, Kamille, additional, Uchida, Naoya, additional, E, Shuyu, additional, Kearney, Lilora, additional, Williams, Cortina, additional, Hartwell, Kirsten, additional, Bosnick, Regina, additional, Panch, Sandhya R., additional, Stroncek, David F., additional, Poston, Leigh, additional, Akel, Salem M., additional, Gupta, Neha, additional, Hankins, Jane S, additional, Fitzhugh, Courtney D., additional, Hsieh, Matthew, additional, Tisdale, John F., additional, and Weiss, Mitchell J., additional

Published
2021
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50. Iron Restriction Alleviates β-Thalassemia By Stimulating ULK1-Mediated Autophagy of Free α-Globin

Author

Fernandez, Alfonso G., Christakopoulos, Georgios E., Michael, Dudley E., Sweileh, Razan B. A., Telange, Rahul, Sheppard, Heather, Yao, Yu, Zhang, Jingjing, Manolova, Vania, Nemeth, Elizabeta, Ganz, Tomas, and Weiss, Mitchell J.

Abstract

In β-thalassemia, mutations in the HBBgene cause reduced β-globin synthesis with accumulation of toxic free α-globin, leading to ineffective erythropoiesis and hemolysis. We showed previously that β-thalassemic erythroblasts can eliminate free α-globin by ULK1-mediated autophagy and that this process is stimulated by rapamycin inhibition of mTORC1, which phosphorylates ULK1 to inhibit its activity. Several studies have shown that iron restriction can reduce the accumulation of free α-globin precipitates to alleviate the pathophysiology of β-thalassemia. Considering that iron stimulates mTORC1 activity in numerous cell types including erythroblasts, we tested the hypothesis that iron restriction alleviates β-thalassemia by inhibiting mTORC1, thereby stimulating ULK1-mediated autophagy of free α-globin.

Published
2023
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