We are seeking to recruit a talented and motivated Postdoctoral Research Scientist to investigate the gene regulatory control of human pluripotent states. This position is within Peter Rugg-Gunn’s team in the Epigenetics Programme at the Babraham Institute, Cambridge, UK.
The central aim of this three-year project is to investigate new regulators of human naïve cell reprogramming that we have recently identified, and to develop a mechanistic understanding of how they function. The job holder will engineer human pluripotent cell lines with inducible degradation systems targeting the identified regulators and will use these cell lines to investigate the molecular and cellular defects that arise following protein degradation. The job holder will also use CUT&Tag methods to identify genome-wide occupancy of the proteins of interest. We have particular expertise in reprogramming and capacitation transitions, developmental cell models including gastruloids, gene targeting, and in relevant assays such as proteomics and single cell transcriptomics / epigenomics. The overall significance of this work will be to establish exciting new links between gene regulatory mechanisms and the control of pluripotency during human development. We anticipate that modulating the identified pathways will improve the generation of naïve cells and open up new ways to deliver cell types with useful translational properties.
The ideal candidate will be interested in stem cell and developmental biology, particularly in the gene regulatory mechanisms that underpin lineage specification and reprogramming. The Epigenetics Programme provides a highly collaborative and thriving research environment with particular strengths in stem cell, developmental and ageing biology. We have access to onsite state-of-the-art facilities run by dedicated staff, including High-Throughput Sequencing, Bioinformatics, Imaging and Gene Targeting. We have close links to Cambridge University through affiliations with the Stem Cell Institute, the Centre for Trophoblast Research, the Epigenetics Club, and with the many departments and companies that we work with.
Multiple positions are available in the Stottmann lab as we relocate to the Institute for Genomic Medicine at Nationwide Children’s Hospital and Ohio State University. We study the genetic basis of structural birth defects. Projects usually focus on novel genes and mutations identified through human whole genome sequencing. We use sequencing analysis and a range of molecular embryological tools including genome editing in animal models and in vitro studies. Candidates will develop a robust research program in close consultation with the PI. We prefer applicants with multiple first-author publications and experience in mouse genetics, molecular biology and/or embryology. We also look for applicants with experience with iPSC culture. More information is at our current web page at Cincinnati Children’s:
The next webinar in our Development presents… series will be chaired by Development editor, Thomas Lecuit (Institut de Biologie du Développment de Marseille). Thomas has brought together three talks on the topic of mechanics and morphogenesis.
The webinar will be held in Remo, our browser-based conferencing platform – after the talks you’ll have the chance to meet the speakers and other participants at virtual conference tables. If you can’t make it on the day, talks will be available to watch for a couple of weeks after the event; details will be posted on the Node or you can sign up to our mailing list for email alerts.
For more information about what to expect in Remo, go to
Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma
Karin D. Prummel, Helena L. Crowell, Susan Nieuwenhuize, Eline C. Brombacher, Stephan Daetwyler, Charlotte Soneson, Jelena Kresoja-Rakic, Manuel Ronner, Agnese Kocere, Alexander Ernst, Zahra Labbaf, David E. Clouthier, Anthony B. Firulli, Héctor Sánchez-Iranzo, Sundar R. Naganathan, Rebecca O’Rourke, Erez Raz, Nadia Mercader, Alexa Burger, Emanuela Felley-Bosco, Jan Huisken, Mark D. Robinson, Christian Mosimann
Long noncoding RNA VENTHEART is required for cardiomyocyte specification and function
Albert Dashi, Wilson L.W. Tan, Chukwuemeka George Anene-Nzelu, Bangfen Pan, Autio Matias Ilmari, Zenia Tiang, Robin J.G. Hartman, Justus Stenzig, Heming Wei, Chen Gao Bin, Matthew Andrew Ackers-Johnson, Bing Lim, Anna Walentinsson, Vidhya Vardharajan Iyer, Malin K.B. Jonsson, Roger S. Foo
Dichotomous regulation of lysosomes by MYC and TFEB controls hematopoietic stem cell fate
Laura García-Prat, Kerstin B. Kaufmann, Florin Schneiter, Veronique Voisin, Alex Murison, Jocelyn Chen, Michelle Chan-Seng-Yue, Olga I. Gan, Jessica L. McLeod, Sabrina A. Smith, Michelle C. Shoong, Darrien Paris, Kristele Pan, Andy G.X. Zeng, Gabriela Krivdova, Kinam Gupta, Shin-Ichiro Takayanagi, Elvin Wagenblast, Weijia Wang, Mathieu Lupien, Timm Schroeder, Stephanie Z. Xie, John E. Dick
Drosophila functional screening of de novo variants in autism uncovers deleterious variants and facilitates discovery of rare neurodevelopmental diseases
Paul C Marcogliese, Samantha L Deal, Jonathan Andrews, J Michael Harnish, V Hemanjani Bhavana, Hillary K Graves, Sharayu Jangam, Xi Luo, Ning Liu, Danqing Bei, Yu-Hsin Chao, Brooke Hull, Pei-Tseng Lee, Hongling Pan, Colleen M Longley, Hsiao-Tuan Chao, Hyunglok Chung, Nele A Haelterman, Oguz Kanca, Sathiya N Manivannan, Linda Z Rossetti, Amanda Gerard, Eva Maria Christina Schwaibold, Renzo Guerrini, Annalisa Vetro, Eleina England, Chaya N Murali, Tahsin Stefan Barakat, Marieke F van Dooren, Martina Wilke, Marjon van Slegtenhorst, Gaetan Lesca, Isabelle Sabatier, Nicolas Chatron, Catherine A Brownstein, Jill A Madden, Pankaj B Agrawal, Roberto Keller, Lisa Pavinato, Alfredo Brusco, Jill A Rosenfeld, Ronit Marom, Michael F Wangler, Shinya Yamamoto
Glutamatergic dysfunction precedes neuron loss in cerebral organoids with MAPT mutation
Kathryn R. Bowles, M. Catarina Silva, Kristen Whitney, Taylor Bertucci, Jacob C. Garza, Nathan C. Boles, Kevin H. Strang, Sidhartha Mahali, Jacob A. Marsh, Cynthia Chen, Derian A. Pugh, Yiyuan Liu, Joshua E. Berlind, Jesse D. Lai, Susan K. Goderie, Rebecca Chowdhury, Steven Lotz, Keith Lane, Khadijah Onanuga, Celeste M. Karch, Justin K. Ichida, John F. Crary, Stephen J. Haggarty, Alison M. Goate, Sally Temple
Developmental and behavioral phenotypes in a new mouse model of DDX3X syndrome
Andrea Boitnott, Dévina C Ung, Marta Garcia-Forn, Kristi Niblo, Danielle Mendonca, Michael Flores, Sylvia Maxwell, Jacob Ellegood, Lily R Qiu, Dorothy E Grice, Jason P Lerch, Mladen-Roko Rasin, Joseph D Buxbaum, Elodie Drapeau, Silvia De Rubeis
A Human Multi-Lineage Hepatic Organoid Model for Liver Fibrosis
Yuan Guan, Annika Enejder, Meiyue Wang, Zhuoqing Fang, Lu Cui, Shih-Yu Chen, Jingxiao Wang, Yalun Tan, Manhong Wu, Xinyu Chen, Patrik K. Johansson, Issra Osman, Koshi Kunimoto, Pierre Russo, Sarah C. Heilshorn, Gary Peltz
The making of cauliflowers: the story of unsuccessful flowers
Eugenio Azpeitia, Gabrielle Tichtinsky, Marie Le Masson, Antonio Serrano-Mislata, Veronica Gregis, Carlos Gimenez, Nathanaёl Prunet, Jérémy Lucas, Etienne Farcot, Martin M. Kater, Desmond Bradley, Francisco Madueño, Christophe Godin, Francois Parcy
Apple ripening is controlled by a NAC transcription factor
Zoë Migicovsky, Trevor H. Yeats, Sophie Watts, Jun Song, Charles F. Forney, Karen Burgher-MacLellan, Daryl J. Somers, Yihi Gong, Zhaoqi Zhang, Julia Vrebalov, James G. Giovannoni, Jocelyn K. C. Rose, Sean Myles
Gene loss during the transition to multicellularity
Berenice Jiménez-Marín, Jessica B. Rakijas, Antariksh Tyagi, Aakash Pandey, Erik R. Hanschen, Jaden Anderson, Matthew G. Heffel, Thomas G. Platt, Bradley J. S. C. Olson
A novel adhesive complex at the base of intestinal microvilli
Christian Hartmann, Eva-Maria Thüring, Birgitta E. Michels, Denise Pajonczyk, Sophia Leußink, Lilo Greune, Frauke Brinkmann, Mark Glaesner-Ebnet, Eva Wardelmann, Thomas Zobel, M. Alexander Schmidt, Volker Gerke, Klaus Ebnet
Developmental patterning is an essential process for multicellular development, as it drives the cell-fate decisions that determine an organism’s body plan. One of the aspects that has fascinated me is the accuracy and reliability of patterning. The accuracy is particularly intriguing because we know this happens in spite of the natural stochasticity that can disrupt biological processes such as tissue patterning. So how do biological systems consistently produce the same pattern with sufficient robustness such that the embryo forms correctly (nearly) every time? This question has been explored by many over the years and several strategies for enhancing developmental robustness have been described. These strategies include redundant gene activation in case of perturbations, cell sorting, preferential adhesion or modifications to the morphogen levels. However, in our recent study we found yet another mechanism, one that functions at a different level of the system, to boost the robustness and the accuracy of tissue patterning.
The study arose as a collaboration between myself, mostly a theoretician at the time, and a fellow student in the lab, Katherine, an experimental biologist (Exelby K et al, 2020). We were studying the vertebrate neural tube. This is often held up as a prime example of a system patterned by a morphogen gradient through positional information in the manner proposed by Lewis Wolpert. My lab had spent many years dissecting the mechanism of neural tube patterning and recent work had been focusing on how signalling gradients are interpreted by a gene regulatory network (GRN) composed of cross-repressive transcription factors (TFs) (Fig. 1 left). A striking feature of neural tube patterning is the sharpness of the borders between gene expression domains that pattern its dorsal-ventral axis. The mechanisms that explain this precision are not well understood. My supervisor, James Briscoe, encouraged Katherine and me to think about some old observations that mutant mice lacking the transcription factor Pax6, one of the genes in the GRN, seemed to disrupt the precision of a boundary between two cell types, the so-called p3 and pMN domains. We repeated these experiments and confirmed that in embryos lacking Pax6 there was a lot more intermixing of cells at this boundary than in wild-type embryos. Importantly, the cell types of each domain were not altered, as the expression of the other components of the GRN remained the same. Furthermore, there is no obvious evidence of a change in cell mobility or adhesion downstream of Pax6. This encouraged us to explore whether this imprecision might be explained by the GRN and how that could happen.
Figure 1. The ventral neural tube is patterned by a cross-repressive GRN that interprets Shh signal (Left). Our stochastic mathematical model captures the behaviour of the system, including position and precision of boundaries in WT and mutants (Right).
We took a mathematical model previously developed in the lab that captures the patterning of the neural tube (Cohen M et al, 2014) and the effects of the various transcription factor knockouts on the patterning. I adapted this model by adding stochasticity, to account for noise in gene expression and degradation. I was pleasantly surprised that just by adding gene expression noise, the model mimicked the loss of precision in patterning seen in the Pax6-/- knockout (Fig. 1 right).
Investigating further, I found that the model suggested altering interaction strength between some of the transcription factors in the GRN could also produce imprecise boundaries. Serendipitously (or perhaps it was good planning), Katherine was experimentally deleting enhancers of some of the transcription factors in the GRN, reasoning that this could alter interaction strengths. She found that when she removed an enhancer for the Olig2 transcription factor (we termed the enhancer O2e33) (is removed), the precision of the p3 and pMN domain was reduced (Fig. 2). The loss of the enhancer did not change the cell types that were generated, it was just that they were more intermixed than normal at the boundary. Just as for the Pax6 mutant, this suggested that corrective mechanisms, such as differential adhesion, probably didn’t explain the precision. Instead, it was consistent with the predictions of the model I had been developing and indicated that the dynamics of gene expression conferred by the GRN play an important role in boundary precision.
Figure 2. O2e33 enhancer upstream of Olig2 sequence, confirmed binding sites from multiple TFs belonging to the patterning GRN (Right). The O2e33 enhancer knockout mutant presents a reduced boundary precision, we capture this behaviour through our model as well as shifts in boundary positions.
So why was this? I set to use the model to understand how the GRN affects boundary precision and I found that the key element was the ease at which one cell type could transition to another. At the boundary between the two domains, the system is bistable (either pMN or p3). Close to this boundary, all cells that achieve a p3 state were previously in a pMN state and switched from pMN through random fluctuations to become p3 (Fig. 3). In the WT system, cells away from the boundary quickly become unable to transition between states by random fluctuations. However, when I simulated cells in the mutant embryos with a modified GRN, I saw that cells retained the ability to transition from pMN to p3 a greater distance away from the boundary and this results in a larger heterogeneous region and thus an imprecise boundary (Fig. 3).
Inspired by the explanation provided by our model, we explored how common it is that a GRN can favour a precise boundary and which networks can do this. Using a computational screen, I systematically explored all possible two and three-node networks that could form networks in response to a graded input and found a consistent pattern. This screen generated many networks that were able to produce sharp boundaries. Looking at these high precision networks, I realised there were two underlying mechanisms, one of which was identical to that used by the neural tube GRN (a detailed explanation is in the paper (Exelby K et al, 2020)).
Figure 3. Transitions from pMN to p3 state determine the pattern. The WT system ensures the area of uncertainty is reduced to a minimum, the area of uncertainty is increased in each of the mutants.
These findings suggest that many real biological networks that produce boundaries appear to be more complex than might be expected, because it allows them to generate sharper boundaries. Indeed, when we examined other networks that regulate patterning through a morphogen signal such as the Drosophila GAP genes or the Drosophila eye disc, we found examples of our high precision networks in each case. The results suggest that there may be a selection of these motifs to favour precision in developmental patterns.
In summary, we found a mechanism by which GRNs simultaneously pattern a tissue and ensure the robustness of such pattern. The precision arises from the structure of the network and is a nice example of an emergent behaviour – it is a consequence of the interactions between the components in the network. We termed this ”precision by design” to reflect the fact that the sharpness of the boundaries was encoded in the GRN. I was delighted that the modelling helped us make experimental predictions and provided an explanation for the results that would otherwise have been opaque. It would not have been easy to pinpoint the mechanism without the years of work from previous theoreticians and experimentalists, allowing me to build onto a well constrained model and develop the project further at the interface between fields. Perhaps most importantly for me, the project really brought home how biological understanding emerges from projects that fully integrate experiments and theoretical modelling. I‚ have now started my post-doc working on cell fate decisions in pre-implantation embryos in the lab of Jean-Léon Maître at Institut Curie. Here, I have started lab work for the first time since my Bachelors degree, and am keen to continue incorporating theory with experiments to tackle interesting question.
Cohen, M, Page, KM, Perez-Carrasco, R, Barnes, CP, & Briscoe, J (2014). A theoretical framework for the regulation of Shh morphogen-controlled gene expression. Development, 141(20), 3868–3878.
Where are you originally from and what do you work on now?
Eva and a surfboard she unleashed her paints on. “During the first lockdown in 2020, I was running out of paper and my housemate let me paint his favourite board.”
I’m from Malaysia and am currently working with Kristian Franze at the University of Cambridge. Here I study the interplay of mechanical and chemical signalling in connecting the nervous system during development. More specifically, I study how axons that originate in the eye respond to chemical and mechanical cues in their environment that help guide their growth towards the visual part of the brain.
Has science always been an important part of your life?
When growing up, I didn’t really know that being a scientist was an option! In fact, I did an Engineering degree before Biology lured me in with its wondrous questions on how life forms and functions. I have always been curious and wanted to know how and why things are the way they are; most children are scientists at heart, guess I never really grew out of that?
And what about art ?
As a kid I loved mixing colours to make ‘new’ ones and doodling (to date, most of my textbooks, papers, and notebooks have doodle-filled margins :p). I don’t have any formal training or education in art. However, rather randomly in the final year of high school I decided to take an art GCSE, it ended up being a fun independent study experience. Since grad school I’ve had a more consistent relationship with art and try to learn a new technique every year.
What or who are your artistic inspirations?
Yayoi Kusama – one could simply disappear in her art! Bill Harris (our previous head of department) – his art hangs in our corridors and sometimes when the going gets tough, I wander out to stare at them and remember how beautiful neurons and the visual system are! And Abhishek Singh – his fabulous depictions of Vedic texts are incredible!
How do you make your art?
It depends on the technique I am playing with. I love mixing my media and enjoy a variety of art forms.
Painting is my spontaneous medium, I allow my hands and eyes to work without thinking or planning. This is the go-to medium in weeks of super structured/planned lab work, it brings me some flow.
Lino-printing is another favourite technique. Printing however relies on some planning and drafting/sketching before I jump into carving the lino. I seem to print more when my work week is less structured (2020 resulted in quite a lot of prints :p).
Does your art influence your science at all, or are they separate worlds?
At present, they are separate worlds that complement each other. While I have illustrated pieces for others science, I feel too close to my current research project to make an art piece of it. Having said that, I rely on my “art eyes” to communicate science, particularly in breaking down complex ideas through simple visual representations. Art practise also trains one to be more observant and detailed, traits that are very handy in the lab!
I rely on my “art eyes” to communicate science
What are you thinking of working on next?
Science-wise, I’m excited to be back in the lab catching up on experiments that couldn’t be done in 2020. I’m also figuring out what I want to work on next. Art-wise, I plan to shift from a 2D to 3D system by trying out clay this year!
Octopus dreams: This illustration was a commission for BlueSci Cambridge (https://www.bluesci.co.uk/), for a piece based on the PBS Nature video of an octopus rapidly changing colour while sleeping. Was it moving through different environments in its sleep? Was it feeling happy? Hungry? Threatened? Living on land?
The Maze: Part of a series of plein air paintings made in the Inner Hebrides. Painting outdoors in the bracing Scottish weather was an interesting challenge.
St John’s College, Cambridge: This was a painting I made of one of my favourite parts of college. St John’s is gorgeous, and I particularly love the flaming autumnal display of Boston Ivy on the back of New Court.
Eva’s paintings
Xenopus laevis: My model organism!
Dionaea muscipula: This piece was inspired by a paper linking signal memory to calcium dynamics in a transgenic Venus flytrap! (paper link: https://www.nature.com/articles/s41477-020-00773-1)
Phylliidae: masters of camouflage. This was part of a month-long ink art series.
Eva’s inks
Little Barn: In 2020 I defended my PhD at home, on Zoom, with a view of the village church from my window. I commemorated this event by making a print of the houses and the church spire peeking out behind.
Solidarity: no one should be afraid of who they love or who they are.
An otter print: carving for a friend who loves otters.
Eva’s lino prints
In memory of John Horton Conway (1937-2020). The portrait is made up of frequently occurring patterns found in The Game of Life
We’re looking for new people to feature in this series throughout the year – whatever kind of art you do, from sculpture to embroidery to music to drawing, if you want to share it with the community just email thenode@biologists.com (nominations are also welcome!).
Stowers Research Conferences are biennial meetings that bring together researchers, faculty, and graduate students to inspire creative thought and collaboration in the basic sciences.
In the latest episode of Genetics Unzipped we’re bringing you some scientific ‘tails’ -literally – as we explore the genetics of dog breeds and behaviour. Is there a gene for being a Very Good Dog or having a boopable snoot? And what happened over tens of thousands of years to turn a fearsome wolf into a pug in a party hat?
We speak with Elinor Karlsson at the University of Massachusetts Medical School and the Broad Institute who’s looking into all aspects of dog genetics, from discovering what gives different breeds their distinctive traits to finding out how genetic variations contribute to psychological characteristics.
Jessica Hekman works with Elinor Karlsson and her team studying the brains and genes of dogs to understand canine behaviour, including trying to figure out why certain dog breeds behave in certain ways.
And Jeff Schoenebeck from the Roslin Institute at the University of Edinburgh has made it his mission to understand how genetic variations contribute to the wide range of shapes and sizes of dog skulls, using CAT scans, as well as lab tests.
If you enjoy the show, please do rate and review on Apple podcasts and help to spread the word on social media. And you can always send feedback and suggestions for future episodes and guests to podcast@geneticsunzipped.com Follow us on Twitter – @geneticsunzip
Ciliopathies are genetic disorders caused by defects in the structure and function of cilia, microtubule-based organelles present on the surface of almost every cell in the human body which play crucial roles in cell signalling. Ciliopathies present a wide range of often severe clinical symptoms, frequently affecting the head and face and leading to conditions such as cleft palate and micrognathia (an underdeveloped lower jaw that can impair feeding and breathing). While we understand many of the genetic causes of human ciliopathies, they are only half the story: the question remains as to why, at a cellular level, defective cilia cause developmental craniofacial abnormalities. Researchers have now discovered that ciliopathic micrognathia in an animal model results from abnormal skeletal differentiation and remodelling. The work from Christian Bonatto Paese, Evan Brooks and others from Samantha Brugmann’s lab at the Cincinnati Children’s Hospital Medical Center in the USA is published in the journal Development.
Surface-rendered whole-mount chick mandibular prominence in wild type chick embryos, stained in blue for DAPI and in red for Sox9, an osteochondroprogenitor marker.
The researchers used the avian ta2 mutant as a model for Oral-Facial-Digital syndrome subtype 14 (OFD14), a rare human ciliopathy characterised by micrognathia. They observed defective formation of the jaw bone (mandible) at early stages of development in ta2 mutants. These defects correlated with unchecked progression through the cell cycle and over-proliferation in skeletal progenitor cells. Importantly, these progenitor cells failed to differentiate into mature osteoblasts (the cells that secrete bone), and this failure of differentiation subsequently led to a reduction in bone deposition and hence micrognathia. The researchers also identified excessive bone resorption, a process which normally contributes to final size and shape of the mandible, as an additional causative factor in the ta2micrognathia. This work informs our understanding of the etiology of human ciliopathic micrognathia.
“We have identified distinct cellular processes that are impaired during the onset of ciliopathic micrognathia,” says Samantha Brugmann. “We know from previous work that these processes are responsive to treatment with pharmacological agents, and we are currently testing a number of these agents to determine if ‘rescuing’ ciliopathic micrognathia is possible. The therapeutic implications are exceptionally real.”
“We are also currently trying to uncover how various organ systems respond to loss of cilia and which molecular and signalling pathways are affected, to continue to advance our understanding of how to tackle treatment for patients,” says Christian Bonatto Paese.
The paper exemplifies how developmental biology can shine a light on devastating genetic disorders. Brugmann concludes: “The most important impact of this study, to me, is how useful basic science and the avian embryo can be towards uncovering mechanisms for human disease.”
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Christian Louis Bonatto Paese, Evan C. Brooks, Megan Aarnio-Peterson, Samantha A. Brugmann. (2020) Ciliopathic micrognathia is caused by aberrant skeletal differentiation and remodeling. Development 2021 148: dev194175 doi: 10.1242/dev.194175 Published 15 February 2021
The 2020 call for the Catalan “Beatriu de Pinós Postdoctoral Fellowships” is now open. This is a fantastic opportunity to join the Araújo group, who are focused on identifying the molecular mechanisms underlying single-cell branching during development and disease. We study this during morphogenesis of the Drosophila melanogaster tracheal and nervous systems (Ricolo et al. Current Biology 2016 and Ricolo and Araújo, eLife, 2020), and are also interested in knowing how single-cell branching affects the whole organismal behaviour. We are combining cell analysis and confocal tissue live imaging, with genetic approaches and CRISPR/Cas9 technologies.
We are based at the Institute of Biomedicine of the University of Barcelona (IBUB) and are looking for a motivated and enthusiastic candidate who will play a central role in the lab. You must have a Ph.D. in areas relevant to cell/developmental biology and/or in computational biology (and have defended your Ph.D. thesis before the 31st of December 2018) and have 2 years postdoctoral experience outside of Spain. Applicants are expected to have excellent interpersonal and communication skills, be highly independent and committed to research in a fast-moving and exciting field.
If you’re interested, please write to sofiajaraujo [at] ub.edu
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