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6. PRC2 Is Required to Maintain Expression of the Maternal Gtl2-Rian-Mirg Locus by Preventing De Novo DNA Methylation in Mouse Embryonic Stem Cells

Author

Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Hendrix, David A., Kellis, Manolis, Das, Partha Pratim, Apostolou, Effie, Buchner, Alice H., Canver, Matthew C., Beyaz, Semir, Ljuboja, Damir, Kuintzle, Rachael, Kim, Woojin, Karnik, Rahul, Shao, Zhen, Xie, Huafeng, Xu, Jian, De Los Angeles, Alejandro, Zhang, Yingying, Choe, Junho, Jun, Don Leong Jia, Shen, Xiaohua, Gregory, Richard I., Daley, George Q., Meissner, Alexander, Hochedlinger, Konrad, Kim, Jonghwan, Orkin, Stuart H., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Hendrix, David A., Kellis, Manolis, Das, Partha Pratim, Apostolou, Effie, Buchner, Alice H., Canver, Matthew C., Beyaz, Semir, Ljuboja, Damir, Kuintzle, Rachael, Kim, Woojin, Karnik, Rahul, Shao, Zhen, Xie, Huafeng, Xu, Jian, De Los Angeles, Alejandro, Zhang, Yingying, Choe, Junho, Jun, Don Leong Jia, Shen, Xiaohua, Gregory, Richard I., Daley, George Q., Meissner, Alexander, Hochedlinger, Konrad, Kim, Jonghwan, and Orkin, Stuart H.

Abstract

DNMT3L, a member of DNA methyltransferases family, is present only in mammals. As it provides specificity to the action of de novo methyltransferases, DNMT3A and DNMT3B and interacts with histone H3, DNMT3L has been invoked as the molecule that can read the histone code and translate it into DNA methylation. It plays an important role in the initiation of genomic imprints during gametogenesis and in nuclear reprogramming. With important functions attributed to it, it is imperative that the DNMT3L expression is tightly controlled. Previously, we had identified a CpG island within the human DNMT3L promoter and first exon that showed loss of DNA methylation in cancer samples. Here we show that this Differentially Methylated CpG island within DNMT3L (DNMT3L DMC) acts to repress transcription, is a Polycomb/Trithorax Response Element (PRE) and interacts with both PRC1 and PRC2 Polycomb repressive complexes. In addition, it adopts inactive chromatin conformation and is associated with other inactive chromatin-specific proteins like SUV39H1 and HP1. The presence of DNMT3L DMC also influences the adjacent promoter to adopt repressive histone post-translational modifications. Due to its association with multiple layers of repressive epigenetic modifications, we believe that PRE within the DNMT3L DMC is responsible for the tight regulation of DNMT3L expression and the aberrant epigenetic modifications of this region leading to DNMT3L overexpression could be the reason of nuclear programming during carcinogenesis., National Institutes of Health (U.S.) (Grant HLBI U01HL100001)

Published
2016

7. PRC2 Is Required to Maintain Expression of the Maternal Gtl2-Rian-Mirg Locus by Preventing De Novo DNA Methylation in Mouse Embryonic Stem Cells

Author

Das, Partha Pratim, primary, Hendrix, David A., additional, Apostolou, Effie, additional, Buchner, Alice H., additional, Canver, Matthew C., additional, Beyaz, Semir, additional, Ljuboja, Damir, additional, Kuintzle, Rachael, additional, Kim, Woojin, additional, Karnik, Rahul, additional, Shao, Zhen, additional, Xie, Huafeng, additional, Xu, Jian, additional, De Los Angeles, Alejandro, additional, Zhang, Yingying, additional, Choe, Junho, additional, Jun, Don Leong Jia, additional, Shen, Xiaohua, additional, Gregory, Richard I., additional, Daley, George Q., additional, Meissner, Alexander, additional, Kellis, Manolis, additional, Hochedlinger, Konrad, additional, Kim, Jonghwan, additional, and Orkin, Stuart H., additional

Published
2015
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8. Distinct and Combinatorial Functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in Mouse Embryonic Stem Cell Identity

Author

Das, Partha Pratim, primary, Shao, Zhen, additional, Beyaz, Semir, additional, Apostolou, Eftychia, additional, Pinello, Luca, additional, Angeles, Alejandro De Los, additional, O’Brien, Kassandra, additional, Atsma, Jennifer Marino, additional, Fujiwara, Yuko, additional, Nguyen, Minh, additional, Ljuboja, Damir, additional, Guo, Guoji, additional, Woo, Andrew, additional, Yuan, Guo-Cheng, additional, Onder, Tamer, additional, Daley, George, additional, Hochedlinger, Konrad, additional, Kim, Jonghwan, additional, and Orkin, Stuart H., additional

Published
2014
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9. PRC2 Is Required to Maintain Expression of the Maternal Gtl2-Rian-MirgLocus by Preventing De Novo DNA Methylation in Mouse Embryonic Stem Cells

Author

Das, Partha Pratim, Hendrix, David A., Apostolou, Effie, Buchner, Alice H., Canver, Matthew C., Beyaz, Semir, Ljuboja, Damir, Kuintzle, Rachael, Kim, Woojin, Karnik, Rahul, Shao, Zhen, Xie, Huafeng, Xu, Jian, De Los Angeles, Alejandro, Zhang, Yingying, Choe, Junho, Jun, Don Leong Jia, Shen, Xiaohua, Gregory, Richard I., Daley, George Q., Meissner, Alexander, Kellis, Manolis, Hochedlinger, Konrad, Kim, Jonghwan, and Orkin, Stuart H.

Abstract

Polycomb Repressive Complex 2 (PRC2) function and DNA methylation (DNAme) are typically correlated with gene repression. Here, we show that PRC2 is required to maintain expression of maternal microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) from the Gtl2-Rian-Mirglocus, which is essential for full pluripotency of iPSCs. In the absence of PRC2, the entire locus becomes transcriptionally repressed due to gain of DNAme at the intergenic differentially methylated regions (IG-DMRs). Furthermore, we demonstrate that the IG-DMR serves as an enhancer of the maternal Gtl2-Rian-Mirglocus. Further analysis reveals that PRC2 interacts physically with Dnmt3 methyltransferases and reduces recruitment to and subsequent DNAme at the IG-DMR, thereby allowing for proper expression of the maternal Gtl2-Rian-Mirglocus. Our observations are consistent with a mechanism through which PRC2 counteracts the action of Dnmt3 methyltransferases at an imprinted locus required for full pluripotency.

Published
2015
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10. When doctors go to business school: career shoices of physician-MBAs.

Author

Ljuboja D, Powers BW, Robbins B, Huckman R, Yeshwant K, and Jain SH

Subjects
Boston, Career Mobility, Databases, Factual, Humans, Practice Patterns, Physicians', Career Choice, Clinical Competence, Commerce education, Education, Medical, Graduate organization & administration, Professional Competence
Abstract

There has been substantial growth in the number of physicians pursing Master of Business Administration (MBA) degrees over the past decade, but there is continuing debate over the utility of these programs and the career outcomes of their graduates. The authors analyzed the clinical and professional activities of a large cohort of physician-MBAs by gathering information on 206 physician graduates from the Harvard Business School MBA program who obtained their degrees between 1941 and 2014. Key outcome measures that were examined include medical specialty, current professional activity, and clinical practice. Chi square tests were used to assess the correlations in the data. Among the careers that were tracked (n = 195), there was significant heterogeneity in current primary employment. The most common sectors were clinical (27.7%), investment banking/finance (27.0%), hospital/provider administration (11.7%), biotech/device/pharmaceutical (10.9%), and entrepreneurship (9.5%). Overall, 84% of physician-MBAs entered residency; approximately half (49.3%) remained clinically active in some capacity and only one-fourth (27.7%) reported clinical medicine as their primary professional role. Among those who pursued residency training, the most common specialties were internal medicine (39.3%), emergency medicine (10.4%), orthopedic surgery (9.2%), and general surgery (8.6%). Physician-MBAs trained in internal medicine were significantly more likely to remain clinically active (63.8% vs 42.4%; P = .01). Clinical activity and primary employment in a clinical role decreased after degree conferment. After completing their education, a majority of physician-MBAs divert their primary professional focus away from clinical activity. These findings reveal new insights into the career outcomes of physician-MBAs.

Published
2016

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