Meena Chakraborty

All Publications

• Increasing equity in science requires better ethics training: A course by trainees, for trainees. Cell genomics Patel, R. A., Ungar, R. A., Pyke, A. L., Adimoelja, A., Chakraborty, M., Cotter, D. J., Freund, M., Goddard, P., Gomez-Stafford, J., Greenwald, E., Higgs, E., Hunter, N., MacKenzie, T. M., Narain, A., Gjorgjieva, T., Martschenko, D. O. 2024: 100554

  Abstract

  Despite the profound impacts of scientific research, few scientists have received the necessary training to productively discuss the ethical and societal implications of their work. To address this critical gap, we-a group of predominantly human genetics trainees-developed a course on genetics, ethics, and society. We intend for this course to serve as a template for other institutions and scientific disciplines. Our curriculum positions human genetics within its historical and societal context and encourages students to evaluate how societal norms and structures impact the conduct of scientific research. We demonstrate the utility of this course via surveys of enrolled students and provide resources and strategies for others hoping to teach a similar course. We conclude by arguing that if we are to work toward rectifying the inequities and injustices produced by our field, we must first learn to view our own research as impacting and being impacted by society.

  View details for DOI 10.1016/j.xgen.2024.100554

  View details for PubMedID 38697124

• Phage-inclusive profiling of human gut microbiomes with Phanta. Nature biotechnology Pinto, Y., Chakraborty, M., Jain, N., Bhatt, A. S. 2023

  Abstract

  Due to technical limitations, most gut microbiome studies have focused on prokaryotes, overlooking viruses. Phanta, a virome-inclusive gut microbiome profiling tool, overcomes the limitations of assembly-based viral profiling methods by using customized k-mer-based classification tools and incorporating recently published catalogs of gut viral genomes. Phanta's optimizations consider the small genome size of viruses, sequence homology with prokaryotes and interactions with other gut microbes. Extensive testing of Phanta on simulated data demonstrates that it quickly and accurately quantifies prokaryotes and viruses. When applied to 245 fecal metagenomes from healthy adults, Phanta identifies ~200 viral species per sample, ~5× more than standard assembly-based methods. We observe a ~2:1 ratio between DNA viruses and bacteria, with higher interindividual variability of the gut virome compared to the gut bacteriome. In another cohort, we observe that Phanta performs equally well on bulk versus virus-enriched metagenomes, making it possible to study prokaryotes and viruses in a single experiment, with a single analysis.

  View details for DOI 10.1038/s41587-023-01799-4

  View details for PubMedID 37231259

  View details for PubMedCentralID 4290017

• Transcription factor antagonism regulates heterogeneity in embryonic stem cell states MOLECULAR CELL Hu, S., Metcalf, E., Mahat, D., Chan, L., Sohal, N., Chakraborty, M., Hamilton, M., Singh, A., Singh, A., Lees, J. A., Sharp, P. A., Garg, S. 2022; 82 (23): 4410-+

  Abstract

  Gene expression heterogeneity underlies cell states and contributes to developmental robustness. While heterogeneity can arise from stochastic transcriptional processes, the extent to which it is regulated is unclear. Here, we characterize the regulatory program underlying heterogeneity in murine embryonic stem cell (mESC) states. We identify differentially active and transcribed enhancers (DATEs) across states. DATEs regulate differentially expressed genes and are distinguished by co-binding of transcription factors Klf4 and Zfp281. In contrast to other factors that interact in a positive feedback network stabilizing mESC cell-type identity, Klf4 and Zfp281 drive opposing transcriptional and chromatin programs. Abrogation of factor binding to DATEs dampens variation in gene expression, and factor loss alters kinetics of switching between states. These results show antagonism between factors at enhancers results in gene expression heterogeneity and formation of cell states, with implications for the generation of diverse cell types during development.

  View details for DOI 10.1016/j.molcel.2022.10.022

  View details for Web of Science ID 000922730600005

  View details for PubMedID 36356583

  View details for PubMedCentralID PMC9722640

• Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2. Cell reports Kim, G., Nakayama, L., Blum, J. A., Akiyama, T., Boeynaems, S., Chakraborty, M., Couthouis, J., Tassoni-Tsuchida, E., Rodriguez, C. M., Bassik, M. C., Gitler, A. D. 2022; 41 (4): 111508

  Abstract

  Mutations in the ataxin-2 gene (ATXN2) cause the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). A therapeutic strategy using antisense oligonucleotides targeting ATXN2 has entered clinical trial in humans. Additional ways to decrease ataxin-2 levels could lead to cheaper or less invasive therapies and elucidate how ataxin-2 is normally regulated. Here, we perform a genome-wide fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen in human cells and identify genes encoding components of the lysosomal vacuolar ATPase (v-ATPase) as modifiers of endogenous ataxin-2 protein levels. Multiple FDA-approved small molecule v-ATPase inhibitors lower ataxin-2 protein levels in mouse and human neurons, and oral administration of at least one of these drugs-etidronate-is sufficient to decrease ataxin-2 in the brains of mice. Together, we propose v-ATPase as a drug target for ALS and SCA2 and demonstrate the value of FACS-based screens in identifying genetic-and potentially druggable-modifiers of human disease proteins.

  View details for DOI 10.1016/j.celrep.2022.111508

  View details for PubMedID 36288714

• Effects of an immersive psychosocial training program on depression and well-being: A randomized clinical trial. Journal of psychiatric research Ganz, A. B., Rolnik, B., Chakraborty, M., Wilson, J., Tau, C., Sharp, M., Reber, D., Slavich, G. M., Snyder, M. P. 2022; 150: 292-299

  Abstract

  Psychiatry stands to benefit from brief non-pharmacological treatments that effectively reduce depressive symptoms. To address this need, we conducted a single-blind randomized clinical trial assessing how a 6-day immersive psychosocial training program, followed by 10-min daily psychosocial exercises for 30 days, improves depressive symptoms. Forty-five adults were block-randomized by depression score to two arms: (a) the immersive psychosocial training program and 10-min daily exercise group (36 days total; total n=23; depressed at baseline n=14); or (b) a gratitude journaling control group (36 days total; total n=22; depressed at baseline n=13). The self-report PHQ-9 was used to assess depression levels in both groups at three time points: baseline, study week one, and study week six. Depression severity improved over time, with a significantly greater reduction in the psychosocial training program group (-82.7%) vs. the control group (-23%), p=0.02 for baseline vs. week six. The effect size for this reduction in depression symptoms was large for the intervention group (d=-1.3; 95% CI, -2.07, -0.45; p<0.001) and small for the control group (d=-0.3; 95% CI, -0.68, 0.03; p=0.22). Seventy-nine percent (11/14) of depressed participants in the intervention condition were in remission (PHQ-9≤4) by week one and 100% (14/14) were in remission at week six. Secondary measures of anxiety, stress, loneliness, and well-being also improved by 15-80% in the intervention group (vs. 0-34% in the control group), ps<0.05. Overall, this brief, immersive psychosocial training program rapidly and substantially improved depression levels and several related secondary outcomes, suggesting that immersive interventions may be useful for reducing depressive symptoms and enhancing well-being.

  View details for DOI 10.1016/j.jpsychires.2022.02.034

  View details for PubMedID 35429739