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 <<<

Abstract All contemporary Eurasians trace most of their ancestry to a small population that dispersed out of Africa about 50,000 years ago (ka)1–9. By contrast, fossil evidence attests to earlier migrations out of Africa10–15. These lines of evidence can only be reconciled if early dispersals made little to no genetic contribution to the later, major wave. A key question therefore concerns what factors facilitated the successful later dispersal that led to long-term settlement beyond Africa. Here we show that a notable expansion in human niche breadth within Africa precedes this later dispersal. We assembled a pan-African database of chronometrically dated archaeological sites and used species distribution models (SDMs) to quantify changes in the bioclimatic niche over the past 120,000 years. We found that the human niche began to expand substantially from 70 ka and that this expansion was driven by humans increasing their use of diverse habitat types, from forests to arid deserts. Thus, humans dispersing out of Africa after 50 ka were equipped with a distinctive ecological flexibility among hominins as they encountered climatically challenging habitats, providing a key mechanism for their adaptive success. <<<

Akanksha Jain, Gilles Gut, Fátima Sanchis-Calleja, Reto Tschannen, Zhisong He, Nicolas Luginbühl, Fides Zenk, Antonius Chrisnandy, Simon Streib, Christoph Harmel, Ryoko Okamoto, Malgorzata Santel, Makiko Seimiya, René Holtackers, Juliane K. Rohland, Sophie Martina Johanna Jansen, Matthias P. Lutolf, J. Gray Camp, Barbara Treutlein <<<

Abstract Brain organoids enable the mechanistic study of human brain development and provide opportunities to explore self-organization in unconstrained developmental systems1–3. Here we establish long-term, live light-sheet microscopy on unguided brain organoids generated from fluorescently labelled human induced pluripotent stem cells, which enables tracking of tissue morphology, cell behaviours and subcellular features over weeks of organoid development4. We provide a novel dual-channel, multi-mosaic and multi-protein labelling strategy combined with a computational demultiplexing approach to enable simultaneous quantification of distinct subcellular features during organoid development. We track actin, tubulin, plasma membrane, nucleus and nuclear envelope dynamics, and quantify cell morphometric and alignment changes during tissue-state transitions including neuroepithelial induction, maturation, lumenization and brain regionalization. On the basis of imaging and single-cell transcriptome modalities, we find that lumenal expansion and cell morphotype composition within the developing neuroepithelium are associated with modulation of gene expression programs involving extracellular matrix pathway regulators and mechanosensing. We show that an extrinsically provided matrix enhances lumen expansion as well as telencephalon formation, and unguided organoids grown in the absence of an extrinsic matrix have altered morphologies with increased neural crest and caudalized tissue identity. Matrix-induced regional guidance and lumen morphogenesis are linked to the WNT and Hippo (YAP1) signalling pathways, including spatially restricted induction of the WNT ligand secretion mediator (WLS) that marks the earliest emergence of non-telencephalic brain regions. Together, our work provides an inroad into studying human brain morphodynamics and supports a view that matrix-linked mechanosensing dynamics have a central role during brain regionalization. <<<

Dirk A. Lamprecht, Richard J. Wall, Annelies Leemans, Barry Truebody, Joke Sprangers, Patricia Fiogbe, Cadi Davies, Jennefer Wetzel, Stijn Daems, William Pearson, Vanessa Pillay, Samantha Saylock, M. Daniel Ricketts, Ellie Davis, Adam Huff, Tsehai Grell, Shiming Lin, Michelle Gerber, Ann Vos, John Dallow, Sam J. Willcocks, Christine Roubert, Stéphanie Sans, Amandine Desorme, Nicolas Chappat, Aurélie Ray, Mariana Pereira Moraes, Tracy Washington, Hope D’Erasmo, Pavankumar Sancheti, Melissa Everaerts, Mario Monshouwer, Jorge Esquivias, Gerald Larrouy-Maumus, Ruxandra Draghia Akli, Helen Fletcher, Alexander S. Pym, Bree B. Aldridge, Jansy P. Sarathy, Kathleen W. Clancy, Bart Stoops, Neeraj Dhar, Adrie J. C. Steyn, Paul Jackson, Clara Aguilar-Pérez, Anil Koul <<<

Yasir Sohail, Chongle Zhang, Dezhen Xue, Jinyu Zhang, Dongdong Zhang, Shaohua Gao, Yang Yang, Xiaoxuan Fan, Hang Zhang, Gang Liu, Jun Sun, En Ma <<<