Li Ping Tang, Li Ming Zhai, Jiming Li, Yue Gao, Qiu Li Ma, Rui Li, Qing Fei Liu, Wen Jie Zhang, Wang Jinsong Yao, Bangbang Mu, Chao Qin, Xin Tian, Rahul Shaw, Keke Xia, Jian Xu, Ying Hua Su, Xian Sheng Zhang <<<

Abstract Waddington’s epigenetic landscape has long served as a conceptual framework for understanding cell fate decisions. The landscape’s geometry encodes the molecular mechanisms that guide the gene expression profiles of uncommitted cells toward terminally differentiated cell types. In this study, we demonstrate that applying the concept of intrinsic dimension to single-cell transcriptomic data can effectively capture trends in expression trajectories, supporting this framework. This approach allows us to define a robust cell potency score without relying on prior biological information. By analyzing an extensive collection of datasets from various species, experimental protocols, and differentiation processes, we validate our method and successfully reproduce established hierarchies of cell type potency. Our work provides a direct link between geometric properties of single-cell expression profiles and the level of differentiation of a cell population. <<<

Jinghui Lei, Zijuan Xin, Ning Liu, Taixin Ning, Ying Jing, Yicheng Qiao, Zan He, Mengmeng Jiang, Yuanhan Yang, Zhiyi Zhang, Liyun Zhao, Jingyi Li, Dongliang Lv, Yupeng Yan, Hui Zhang, Lingling Xiao, Baohu Zhang, Haoyan Huang, Shuhui Sun, Fangshuo Zheng, Xiaoyu Jiang, Huifen Lu, Xueda Dong, Shasha Yue, Chencan Ma, Jichen Shuai, Zhejun Ji, Feifei Liu, Yanxia Ye, Kaowen Yan, Qinchao Hu, Gang Xu, Qian Zhao, Ruochen Wu, Yusheng Cai, Yanling Fan, Yaobin Jing, Qiaoran Wang, Pradeep Reddy, Xiaoyong Lu, Zikai Zheng, Beibei Liu, Amin Haghani, Shuai Ma, Keiichiro Suzuki, Concepcion Rodriguez Esteban, Jiayin Yang, Moshi Song, Steve Horvath, Weiqi Zhang, Wei Li, Andy Peng Xiang, Lan Zhu, Xiaobing Fu, Guoguang Zhao, Juan Carlos Izpisua Belmonte, Jing Qu, Si Wang, Guang-Hui Liu <<<

Juan L. Gomez, Christopher J. Magnus, Jordi Bonaventura, Oscar Solis, Fallon P. Curry, Marjorie R. Levinstein, Reece C. Budinich, Meghan L. Carlton, Emilya N. Ventriglia, Sherry Lam, Le Wang, Ingrid Schoenborn, William Dunne, Michael Michaelides, Scott M. Sternson <<<

Abstract Chemical feedback is ubiquitous in physiology but is challenging to study without perturbing basal functions. One example is addictive drugs, which elicit a positive-feedback cycle of drug-seeking and ingestion by acting on the brain to increase dopamine signalling1–3. However, interfering with this process by altering basal dopamine also adversely affects learning, movement, attention and wakefulness4. Here, inspired by physiological control systems, we developed a highly selective synthetic physiology approach to interfere with the positive-feedback cycle of addiction by installing a cocaine-dependent opposing signalling process into this body–brain signalling loop. We used protein engineering to create cocaine-gated ion channels that are selective for cocaine over other drugs and endogenous molecules. Expression of an excitatory cocaine-gated channel in the rat lateral habenula, a brain region that is normally inhibited by cocaine, suppressed cocaine self-administration without affecting food motivation. This artificial cocaine-activated chemogenetic process reduced the cocaine-induced extracellular dopamine rise in the nucleus accumbens. Our results show that cocaine chemogenetics is a selective approach for countering drug reinforcement by clamping dopamine release in the presence of cocaine. In the future, chemogenetic receptors could be developed for additional addictive drugs or hormones and metabolites, which would facilitate efforts to probe their neural circuit mechanisms using a synthetic physiology approach. As these chemogenetic ion channels are specific for cocaine over natural rewards, they may also offer a route towards gene therapies for cocaine addiction. <<<

Iain S. Forrest, Ha My T. Vy, Ghislain Rocheleau, Daniel M. Jordan, Ben O. Petrazzini, Girish N. Nadkarni, Judy H. Cho, Mythily Ganapathi, Kuan-Lin Huang, Wendy K. Chung, Ron Do <<<

Accurate variant penetrance estimation is crucial for precision medicine. We constructed machine learning (ML) models for 10 diseases using 1,347,298 participants with electronic health records, then applied them to an independent cohort with linked exome data. Resulting probabilities were used to evaluate ML penetrance of 1648 rare variants in 31 autosomal dominant disease-predisposition genes. ML penetrance was variable across variant classes, but highest for pathogenic and loss-of-function variants, and was associated with clinical outcomes and functional data. Compared with conventional case-versus-control approaches, ML penetrance provided refined quantitative estimates and aided the interpretation of variants of uncertain significance and loss-of-function variants by delineating clinical trajectories over time. By leveraging ML and deep phenotyping, we present a scalable approach to accurately quantify disease risk of variants. <<<

Penadés JR, Gottweis J, He L, Patkowski JB, Daryin A, Weng WH, Tu T, Palepu A, Myaskovsky A, Pawlosky A, Natarajan V, Karthikesalingam A, Costa TRD <<<

Miranda V. Hunter, Eshita Joshi, Sydney Bowker, Emily Montal, Yilun Ma, Young Hun Kim, Zhifan Yang, Laura Tuffery, Zhuoning Li, Eric Rosiek, Alexander Browning, Reuben Moncada, Itai Yanai, Helen Byrne, Mara Monetti, Elisa de Stanchina, Pierre-Jacques Hamard, Richard P. Koche, Richard M. White <<<

Abstract Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes: proliferative versus invasive states1,2. Although it has long been hypothesized that such switching is triggered by external cues, the identity of these cues remains unclear. Here we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of interface cells showed elliptical nuclei, suggestive of mechanical confinement by the adjacent tissue. Spatial and single-cell transcriptomics demonstrated that interface cells adopted a gene program of neuronal invasion, including the acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs the contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug-resistant. Our results implicate the mechanical microenvironment as a mechanism that drives phenotype switching in melanoma. <<<

Elaine Huang, Ting Fu, Ling Zhang, Guanao Yan, Ryo Yamamoto, Sari Terrazas, Thuy Linh Nguyen, Carlos Gonzalez-Figueroa, Armen Khanbabaei, Jae Hoon Bahn, Rajagopal Varada, Kofi Amoah, Jonatan Hervoso, Michelle T. Paulsen, Brian Magnuson, Mats Ljungman, Jingyi Jessica Li, Xinshu Xiao <<<

Andrew J. Scott, Anjali Mittal, Baharan Meghdadi, Alexandra O’Brien, Justine Bailleul, Palavalasa Sravya, Abhinav Achreja, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Ningning Liang, Ayesha U. Kothari, Navyateja Korimerla, Donna M. Edwards, Zhe Wu, Jiane Feng, Sophia Su, Li Zhang, Peter Sajjakulnukit, Anthony C. Andren, Junyoung O. Park, Johanna ten Hoeve, Vijay Tarnal, Kimberly A. Redic, Nathan R. Qi, Joshua L. Fischer, Ethan Yang, Michael S. Regan, Sylwia A. Stopka, Gerard Baquer, Krithika Suresh, Jann N. Sarkaria, Theodore S. Lawrence, Sriram Venneti, Nathalie Y. R. Agar, Erina Vlashi, Costas A. Lyssiotis, Wajd N. Al-Holou, Deepak Nagrath, Daniel R. Wahl <<<

Over time, cells in the brain and in the body accumulate damage, which contributes to the ageing process. In the human brain, the prefrontal cortex undergoes age-related changes that can affect cognitive functioning later in life. Here, using single-nucleus RNA sequencing (snRNA-seq), single-cell whole-genome sequencing (scWGS) and spatial transcriptomics, we identify gene-expression and genomic changes in the human prefrontal cortex across lifespan, from infancy to centenarian. snRNA-seq identified infant-specific cell clusters enriched for the expression of neurodevelopmental genes, as well as an age-associated common downregulation of cell-essential homeostatic genes that function in ribosomes, transport and metabolism across cell types. Conversely, the expression of neuron-specific genes generally remains stable throughout life. These findings were validated with spatial transcriptomics. scWGS identified two age-associated mutational signatures that correlate with gene transcription and gene repression, respectively, and revealed gene length- and expression-level-dependent rates of somatic mutation in neurons that correlate with the transcriptomic landscape of the aged human brain. Our results provide insight into crucial aspects of human brain development and ageing, and shed light on transcriptomic and genomic dynamics. <<<

Abstract Embryonic development follows a conserved sequence of events across species, yet the pace of development is highly variable and particularly slow in humans. Species-specific developmental timing is largely recapitulated in stem cell models, suggesting a cell-intrinsic clock. Here we use directed differentiation of human embryonic stem cells into neuroectoderm to perform a whole-genome CRISPR-Cas9 knockout screen and show that the epigenetic factors Menin and SUZ12 modulate the speed of PAX6 expression during neural differentiation. Genetic and pharmacological loss-of-function of Menin or SUZ12 accelerate cell fate acquisition by shifting the balance of H3K4me3 and H3K27me3 at bivalent promoters, thereby priming key developmental genes for faster activation upon differentiation. We further reveal a synergistic interaction of Menin and SUZ12 in modulating differentiation speed. The acceleration effects were observed in definitive endoderm, cardiomyocyte and neuronal differentiation paradigms, pointing to chromatin bivalency as a general driver of timing across germ layers and developmental stages. <<<

Nadine Serhan, Nasser S. Abdullah, Nadine Gheziel, Alexia Loste, Rüçhan Ekren, Elodie Labit, Anne-Alicia Gonzalez, Giulia Oliva, Pauline Tarot, Camille Petitfils, Gaëlle Payros, Paolo D’Avino, Allison Voisin, Holly Freya Grace Tinsley, Rebecca Gentek, Carole Brosseau, Marie Bodinier, Laurent Reber, Pierre Val, Cezmi A. Akdis, Yasutaka Mitamura, Anand Kumar Andiappan, Jerry Kok Yen Chan, Florent Ginhoux, Amaury François, Nicolas Cénac, Lilian Basso, Nicolas Gaudenzio <<<

Gayani Senevirathne, Serena C. Fernandopulle, Daniel Richard, Stephanie L. Baumgart, Anika Liv Christensen, Matteo Fabbri, Jakob Höppner, Harald Jüppner, Peishu Li, Vivien Bothe, Nadia Fröbisch, Ian Simcock, Owen J. Arthurs, Alistair Calder, Naomi Freilich, Niamh C. Nowlan, Ian A. Glass, April Craft, Terence D. Capellini <<<

Emily Grist, Peter Dutey-Magni, Marina A. Parry, Larissa Mendes, Ashwin Sachdeva, James A. Proudfoot, Anis A. Hamid, Mazlina Ismail, Sarah Howlett, Stefanie Friedrich, Lia DePaula Oliveira, Laura Murphy, Christopher Brawley, Oluwademilade Dairo, Sharanpreet Lall, Yang Liu, Daniel Wetterskog, Anna Wingate, Karolina Nowakowska, Leila Zakka, Claire L. Amos, Nafisah B. Atako, Victoria Wang, Hannah L. Rush, Robert J. Jones, Hing Leung, William R. Cross, Silke Gillessen, Chris C. Parker, Teresa Marafioti, Alfonso Urbanucci, Matthew Fittall, Edward M. Schaeffer, Daniel E. Spratt, David Waugh, Thomas Powles, Matthew R. Sydes, Felix Y. Feng, Daniel M. Berney, Mahesh K.B. Parmar, Noel W. Clarke, Elai Davicioni, Tamara L. Lotan, Christopher J. Sweeney, Louise C. Brown, Nicholas D. James, Gerhardt Attard <<<

Weiran Feng, Erik Ladewig, Matthew Lange, Nazifa Salsabeel, Huiyong Zhao, Young Sun Lee, Anuradha Gopalan, Hanzhi Luo, Wenfei Kang, Ning Fan, Eric Rosiek, Elisa de Stanchina, Yu Chen, Brett S. Carver, Christina S. Leslie, Charles L. Sawyers <<<

Abstract Despite the high prevalence of ERG transcription factor translocations in prostate cancer, the mechanism of tumorigenicity remains poorly understood. Using lineage tracing, we find the tumor-initiating activity of ERG resides in a subpopulation of murine basal cells that coexpress luminal genes (BasalLum) and not in the larger population of ERG+ luminal cells. Upon ERG activation, BasalLum cells give rise to highly proliferative intermediate (IM) cells with stem-like features that coexpress basal, luminal, hillock and club marker genes, before transitioning to Krt8+ luminal cells. Transcriptomic analysis of ERG+ human prostate cancers confirms the presence of rare ERG+ BasalLum cells, as well as IM cells whose presence is associated with a worse prognosis. Single-cell analysis revealed a chromatin state in ERG+ IM cells enriched for STAT3 transcription factor binding sites and elevated expression of the KMT2A/MLL1 and DOT1L, all three of which are essential for ERG-driven tumorigenicity in vivo. In addition to providing translational opportunities, this work illustrates how single-cell approaches combined with lineage tracing can identify cancer vulnerabilities not evident from bulk analysis. <<<

Michael Kosicki, Boyang Zhang, Vivian Hecht, Anusri Pampari, Laura E. Cook, Neil Slaven, Jennifer A. Akiyama, Ingrid Plajzer-Frick, Catherine S. Novak, Momoe Kato, Stella Tran, Riana D. Hunter, Kianna von Maydell, Sarah Barton, Erik Beckman, Yiwen Zhu, Diane E. Dickel, Anshul Kundaje, Axel Visel, Len A. Pennacchio <<<