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Remembering Michael R. Green (1954-2023): An eminent biologist who broke the monotony of mammalian transcription

Michael R. Green was a world-renowned molecular biologist whose ideas and discoveries revolutionized how we understand gene expression today. In his career, Michael provided a remarkable proportion of the fundamental knowledge of pre-mRNA splicing, one of the steps in processing RNA, and viral and eukaryotic transcription, the process by which a cell makes an RNA copy of a piece of DNA.

Michael earned his MD and PhD degrees from Washington University School of Medicine, carried out his postdoctoral and early career work at Harvard University, and finally settled at UMass Chan Medical School in 1990. For over three decades, Michael served in multiple leadership, administrative, and teaching roles at UMass Chan Medical School, a vice provost for strategic research initiatives, professor and chair of molecular, cell and cancer biology, director of the UMass Cancer Center, co-director of the Li Weibo Institute for Rare Diseases Research, and the Lambi and Sarah Adams Chair in Genetic Research.

His scientific contributions in the fields of pre-mRNA splicing, transcription, and cancer biology led to his election to the world’s most prestigious academies: the National Academy of Sciences (2014), the National Academy of Medicine (2015), and the American Academies of Arts and Sciences (2018), in addition to the European Molecular Biology Organization (2010) and Howard Hughes Medical Institute (1994-2018). He was awarded several prestigious research awards for his scientific breakthroughs, including the Presidential Young Investigators Award (1985), the Searle Scholar Award (1986), and the McKnight Neuroscience Award (1991), and in 1993, he delivered a Harvey Lecture (Green, 1992).

Michael applied his expertise in basic transcription mechanisms to identify and analyze epigenetic pathways, which control gene activity without changing the DNA sequence. He sought to understand how alterations in gene regulation cause and impact cancer, rare genetic disorders, and a wide range of other human diseases. Michael’s seminal research united the fields of molecular biology, genetics, and genomics, identifying new cancer-causing genes (oncogenes; (Bhatnagar et al., 2014a)), and cancer-suppressing genes (tumor suppressors; (Fang et al., 2015; Gobeil et al., 2008)).

Michael was always ahead of his time, and recognized early on that cancer and other diseases could arise due to the inappropriate transcriptional inactivation of specific genes. He identified numerous factors and pathways involved in silencing tumor suppressors (Fang et al., 2016; Palakurthy et al., 2009; Wajapeyee et al., 2013; Xie et al., 2012). These findings have singularly ruled out the previously favored tumor suppressor gene silencing model, which posits that repressive epigenetic marks are randomly acquired and selected because they confer a growth advantage.

Michael was brilliant in pivoting the lessons learned from reactivating silenced tumor suppressors in the cancer cell to find a cure for diseases caused by a single gene, whose reactivation could be a therapeutic approach. His passion and enthusiasm for discovery paved the way for a novel X-reactivation-based therapeutic approach for rare monogenic disorders, such as Rett syndrome, which is caused by a defective X-linked gene called MECP2. He noted in a 2014 inaugural article in The Proceedings of the National Academy of Sciences that cellular factors, not previously thought of, are required for silencing of the inactive X chromosome, and small molecule inhibitors of these factors can reactivate the wild-type MECP2 gene from the inactive X (Bhatnagar et al., 2014b). Contradictory to the bulk of the work in the X-inactivation field at the time, this work overturned the longstanding assumption that X-inactivation is irreversible and could be achieved pharmacologically. In recent years, he extended these results to tackle other rare monogenic disorders such as Fragile X Syndrome and Friedreich Ataxia.

Beloved and respected by his colleagues and trainees, Michael positively impacted many lives along the way with his larger-than-life personality, intellect, and quick wit. Many of us lucky enough to have trained or worked with him almost certainly have stories that remind us of Michael’s discipline, persistence, curiosity, and enthusiasm even today.

I got to know Michael when I joined his group, the Green lab, as a postdoctoral fellow in 2008. From the beginning, it was clear that he was a man who pushed the limits in his intellectual and professional life. His unerring eye for critical clinical problems and ability to think outside the box left many in awe. Michael was a generous mentor, but his directness and no-nonsense attitude were central to his mentoring style.

The lab environment was competitive and intense in a good and fun way. Lab meetings were long and never canceled (not even during an epic New England snowstorm), and they were always open for discussions, almost always led by Michael. “Do not get emotionally attached to a project,” was his advice to drive us to think critically and logically. There was no sugarcoating of hard truths and failed projects, but there was full support to address the problems and move forward. In the most challenging times and when the stakes were highest, I found him the most supportive and biggest cheerleader on the sidelines. Over the years in his lab, and even after moving on, Michael always encouraged and guided me, and I can say that this was the same for numerous PhD and postdoctoral trainees and staff who passed through the Green lab.

When I moved toward my goal of being an independent investigator, he encouraged and supported me through the process. I am indebted for his honest and generous mentorship that allowed me to take on the adventures of an independent investigator. The mentoring didn’t end with the training in his lab for him. He stayed in touch with several of us, even after moving on to new jobs. We were fortunate to have his continued scientific input, professional advice, and invaluable feedback on grants and manuscripts. Michael wrote numerous recommendation letters for jobs, merits, promotions, visa/green card applications, and tenure for several of us. Despite being extremely busy, the turnaround time for the request was under five minutes, and always, “Will do.”

As the scientific world says farewell to Michael Green, we, the past and current Green lab members, will miss him tremendously. Fittingly, as Dr. Claude Gazin, a former visiting scientist in the lab, said, “We are like a family, who lost a father” — maybe metaphorically, but it does capture the mood in the Green lab family.

His legacy will live on in the Lazare Research Building hallways and through his students and former trainees spread across the globe. He will always be the G.O.A.T. for the Green lab family, present and past members.

We will miss you, Michael!

P.S. Thanks, Monica Coenraads, for giving me this opportunity to comment on Michael’s
achievements and scientific legacy. Also, thanks to the Green lab family for sharing their

Bhatnagar, S., Gazin, C., Chamberlain, L., Ou, J., Zhu, X., Tushir, J.S., Virbasius, C.M., Lin, L., Zhu, L.J., Wajapeyee, N., et al. (2014a). TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein. Nature 516, 116-120.
Bhatnagar, S., Zhu, X., Ou, J., Lin, L., Chamberlain, L., Zhu, L.J., Wajapeyee, N., and Green, M.R. (2014b). Genetic and pharmacological reactivation of the mammalian inactive X chromosome. Proc Natl Acad Sci U S A 111, 12591-12598.

Fang, M., Hutchinson, L., Deng, A., and Green, M.R. (2016). Common BRAF(V600E)-directed pathway mediates widespread epigenetic silencing in colorectal cancer and melanoma. Proc Natl Acad Sci U S A 113, 1250-1255.

Fang, M., Pak, M.L., Chamberlain, L., Xing, W., Yu, H., and Green, M.R. (2015). The CREB Coactivator CRTC2 Is a Lymphoma Tumor Suppressor that Preserves Genome Integrity through Transcription of DNA Mismatch Repair Genes. Cell Rep 11, 1350-1357.

Gobeil, S., Zhu, X., Doillon, C.J., and Green, M.R. (2008). A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene. Genes Dev 22, 2932-2940.

Green, M.R. (1992). Cellular and viral transcriptional activators. Harvey Lect 88, 67-96.

Palakurthy, R.K., Wajapeyee, N., Santra, M.K., Gazin, C., Lin, L., Gobeil, S., and Green, M.R. (2009). Epigenetic silencing of the RASSF1A tumor suppressor gene through HOXB3-mediated induction of DNMT3B expression. Mol Cell 36, 219-230.

Wajapeyee, N., Malonia, S.K., Palakurthy, R.K., and Green, M.R. (2013). Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors. Genes Dev 27, 2221-2226.

Xie, L., Gazin, C., Park, S.M., Zhu, L.J., Debily, M.A., Kittler, E.L., Zapp, M.L., Lapointe, D., Gobeil, S., Virbasius, C.M., et al. (2012). A synthetic interaction screen identifies factors selectively required for proliferation and TERT transcription in p53-deficient human cancer cells. PLoS Genet 8, e1003151.