Fridolin Gross

University of Bordeaux · Biological and medical sciences

Drugs targeting microtubules rely on the mitotic checkpoint to arrest cell proliferation. The prolonged mitotic arrest induced by such drugs is followed by a G1 arrest. Here, we follow for several weeks the fate of G1-arrested human cells after treatment with nocodazole. We find that a small fraction of cells escapes from the arrest and resumes pro...

Bipolar disorder (BD) is a chronic mood disorder characterized by manic and depressive episodes. Dysregulation of neuroplasticity and calcium homeostasis are frequently observed in BD patients, but the underlying molecular mechanisms are largely unknown. Here, we show that miR-499-5p regulates dendritogenesis and cognitive function by downregulatin...

Motivation microRNAs are important post-transcriptional regulators of gene expression, but the identification of functionally relevant targets is still challenging. Recent research has shown improved prediction of microRNA-mediated repression using a biochemical model combined with empirically-derived k-mer affinity predictions, however these findi...

The Kaposi’s sarcoma associated herpesvirus protein ORF45 binds the extracellular signal-regulated kinase (ERK) and the p90 Ribosomal S6 kinase (RSK). ORF45 was shown to be a kinase activator in cells but a kinase inhibitor in vitro, and its effects on the ERK-RSK complex are unknown. Here, we demonstrate that ORF45 binds ERK and RSK using optimize...

Even though complexity is a concept that is ubiquitously used by biologists and philosophers of biology, it is rarely made precise. I argue that a clarification of the concept is neither trivial nor unachievable, and I propose a unifying framework based on the technical notion of “effective complexity” that allows me to do justice to conflicting in...

Cells with blocked microtubule polymerization are delayed in mitosis, but eventually manage to proliferate despite substantial chromosome missegregation. While several studies have analyzed the first cell division after microtubule depolymerization, we have asked how cells cope long-term with microtubule impairment. We allowed 24 clonal populations...

Single traumatic events that elicit an exaggerated stress response can lead to the development of neuropsychiatric conditions. Rodent studies suggested germline RNA as a mediator of effects of chronic environmental exposures to the progeny. The effects of an acute paternal stress exposure on the germline and their potential consequences on offsprin...

Despite the importance of microRNAs (miRNAs) in regulating a broad variety of biological processes, accurately predicting the transcripts they repress remains a challenge. Recent research suggests improved miRNA target prediction using a biochemical model combined with empirically-derived affinity predictions across 12mer sequences. Here, we transl...

Bipolar disorder (BD) is a chronic mood disorder characterized by alternating manic and depressive episodes, often in conjunction with cognitive deficits. Dysregulation of neuroplasticity and calcium homeostasis as a result of complex genetic environment interactions are frequently observed in BD patients, but the underlying molecular mechanisms ar...

Bipolar disorder (BD) is a chronic mood disorder characterized by alternating manic and depressive episodes, often in conjunction with cognitive deficits. Dysregulation of neuroplasticity and calcium homeostasis as a result of complex genetic environment interactions are frequently observed in BD patients, but the underlying molecular mechanisms ar...

Single traumatic events that elicit an exaggerated stress response can lead to the development of neuropsychiatric conditions. Studies in mice suggests germline RNA as a mediator of effects of chronic environmental exposures to the progeny. The effects of an acute paternal stress exposure on the germline and their potential consequences on offsprin...

One of the many peculiar phenomena that the Covid-19 pandemic has brought about is the engagement of non-scientists with specific questions surrounding the interpretation of epidemiological data and models. Many of them have even begun to get involved in the collection, analysis, and presentation of the data themselves. A reason for this might be t...

Microtubules, polymers of alpha- and beta-tubulin, are essential cellular components. When microtubule polymerization is hindered, cells are delayed in mitosis, but eventually they manage to proliferate with massive chromosome missegregation. Several studies have analyzed the first cell division upon microtubules impairing conditions. Here, we aske...

Computational methods have become increasingly prevalent in molecular biology over the last decades. While this development has been met with mixed expectations, everyone appears to agree that we are witnessing a deep transformation of the epistemic and methodological conditions of the life sciences. In this contribution I would like to investigate...

PP1 and PP2A-B56 are major serine/threonine phosphatase families that achieve specificity by colocalizing with substrates. At the kinetochore, however, both phosphatases localize to an almost identical molecular space and yet they still manage to regulate unique pathways and processes. By switching or modulating the positions of PP1/PP2A-B56 at kin...

Occam’s razor refers to the idea that among competing explanations the simplest should be preferred. This principle has been understood and defended in different ways. Some systems biologists argue that traditional molecular biology is misguided because it relies on an unjustified application of Occam’s razor. I analyze which version of the princip...

Eukaryotic cells treated with microtubule-targeting agents activate the spindle assembly checkpoint to arrest in mitosis and prevent chromosome mis-segregation. A fraction of mitotically arrested cells overcomes the block and proliferates even under persistent checkpoint-activating conditions. Here, we asked what allows proliferation in such unfavo...

PP1 and PP2A are the two main serine/threonine phosphatase families in eukaryotic cells and yet there is no unifying theory to explain how they integrate phosphorylation signals differently. We show here that removal of either PP1 or PP2A-B56 from the kinetochore produces dramatically different phenotypes, but surprisingly, artificial recruitment s...

We present two case studies from contemporary biology in which we observe conflicts between established and emerging approaches. The first case study discusses the relation between molecular biology and systems biology regarding the explanation of cellular processes, while the second deals with phylogenetic systematics and the challenge posed by re...

The mitotic checkpoint (also called spindle assembly checkpoint) is a signaling pathway that ensures faithful chromosome segregation. Mitotic checkpoint proteins inhibit the anaphase-promoting complex (APC/C) and its activator Cdc20 to prevent precocious anaphase. Checkpoint signaling leads to a complex of APC/C, Cdc20, and checkpoint proteins, in...

“In general there is a risk that mathematical modeling, very much like statistics, turns into a large toolbox that is unmanageable for all but the most experienced scholars because there is no manual that helps them to choose the right tool. The prospect for progress in this regard is difficult to evaluate. For philosophers to actually contribute,...

Improperly attached chromosomes activate the mitotic checkpoint that arrests cell division before anaphase. Cells can maintain an arrest for several hours but eventually will resume proliferation, a process we refer to as adaptation. Whether adapting cells bypass an active block or whether the block has to be removed to resume proliferation is not...

Systems biologists often distance themselves from reductionist approaches and formulate their aim as understanding living systems “as a whole.” Yet, it is often unclear what kind of reductionism they have in mind, and in what sense their methodologies would offer a superior approach. To address these questions, we distinguish between two types of re...

There are currently no widely shared criteria by which to assess the validity of computational models in systems biology. Here we discuss the feasibility and desirability of implementing validation standards for modeling. Having such a standard would facilitate journal review, interdisciplinary collaboration, model exchange, and be especially relev...

Parameter estimates for the mathematical model. Parameter names, symbols and values used for the mathematical modeling are given. DOI: http://dx.doi.org/10.7554/eLife.20616.015

The IL-2/IL-2Ralpha (CD25) axis is of central importance for the interplay of effector and regulatory T cells. Nevertheless, the question how different antigen loads are translated into appropriate IL-2 production to ensure adequate responses against pathogens remains largely unexplored. Here we find that at single cell level, IL-2 is binary (digit...

Transcription factors of the nuclear factor of activated T cell (NFAT)-family are essential for antigen-specific T cell activation and differentiation. Their cooperative DNA binding with other transcription factors, such as AP1-proteins (FOS, JUN, JUNB), FOXP3, IRFs and EGR1, dictate the gene regulatory action of NFATs. To identify as yet unknown i...

Transcription factors (TFs) regulate cell type-specific gene expression programs by combinatorial binding to cis-genomic elements, particularly enhancers, subsequently leading to the recruitment of cofactors and the general transcriptional machinery to target genes. Using data integration of genome-wide TF binding profiles we defined regions with c...

In this chapter I investigate explanations in systems biology that rely on dynamical models of biological systems. I argue that accounts of mechanistic explanation cannot easily make sense of certain features of dynamical patterns if they restrict themselves to change-relating relationships. When investigating the use of such models, one has to dis...

The spindle checkpoint arrests cells in metaphase until all chromosomes are properly attached to the chromosome segregation machinery. Thereafter, the anaphase promoting complex (APC/C) is activated and chromosome segregation can take place. Cells remain arrested in mitosis for hours in response to checkpoint activation, but not indefinitely. Event...

Current adress for Alessandro Blasimme: INSERM UMR 1027, Université de Toulouse 3-Paul Sabatier

Establishment of iPSC clones upon genome-wide erasure of H3K27me3 at the onset of reprogramming. A. H3K27me3 and p16Ink4a protein levels measured by Western blot analysis in representative populations of TAT-cre transduced Ezh2 control (+/ΔSET) and mutant (ΔSET/ΔSET) MEF after two passages and 11 days of culture. As comparison, representative contr...

Identification of MEF specific genes by cDNA microarray analysis. Heat map representation of the average expression profile of MEF coming from 3 different embryos, 4 Ezh2 control (+/+) iPSC clones and 4 Ezh2 mutant (ΔSET/ΔSET) iPSC clones. Shown are the expression levels of 3644 genes differentially expressed between iPSCs and MEFs (p-value = 0.05;...

qPCR results of H3, H3K4me3, H3K27me3, H3K27me2, and H3K27me1 ChIP on promoters of 17 MEF-specific genes in two representative Ezh2 control (+/+, grey bars) and mutant (ΔSET/ΔSET, purple bars) iPSC clones. Data are represented as fold change of input. The same analysis was performed using unrelated IgG for the ChIP assays. Averages and standard dev...

Molecular and biochemical characterization of Ezh2 mutant iPSC clones. A. Flow cytometric analysis of Ezh2 control (+/ΔSET, upper row) and mutant (ΔSET/ΔSET, lower row) MEF infected with STEMCCA, rtTA and GFP-expressing lentiviruses in two replicate experiments (left and right panel). MEF are gated according to cell size (FSC) and GFP expression. N...

Epigenetic characterization of Ezh2ΔSET/ΔSET iPSCs. A. Analysis of transcript levels (qRT-PCR) and status of PRC2 (SUZ12), H3K27me2 and H3K27me1 (ChIP q-PCR) enrichment at promoters of 17 genes overexpressed in MEF vs. iPSC. For all analyses, two Ezh2 control (+/+; grey) iPSC clones were compared to two mutant (ΔSET/ΔSET; purple) counterparts. Leve...

Targets of H3K27me3 in Ezh2 mutant iPSC are enriched for transcriptional regulators and developmental determinants. A. Tree diagram representing the main steps that lead to the identification of 175 genes that acquired H3K27me3 de novo in the MEF to iPSC transition. See main text for further explanation. B Gene ontology analysis of de novo H3K27 tr...

qRT-PCR analysis of transcript levels in two representative Ezh2+/+ (# 40A7 and # 40A8) and Ezh2ΔSET/ΔSET(# 48B4 and # 48B7) iPSC clones, of a selected list of genes controlling stem cell pluripotency, self renewal and differentiation. Transcript levels were also measured in ESC and MEF. Data are represented as dCts relative to the geometric mean o...

List of antibodies used for immunohistochemistry. (DOCX)

List of antibodies used for Western blot, ChIP, and flow cytometry. (DOCX)

List of primers used for ChIP–qPCR and genotyping. (DOCX)

Supporting information on ChIP–seq and mass spectrometry analyses. (DOCX)

Author Summary Multicellular organisms are composed of a variety of cell types. Over the last years we have learned that cell differentiation is fully reversible and that it takes few specific transcription factors (proteins that bind to DNA and regulate gene expression) to convert one cell type into another. The most dramatic example is the reprog...

A recent debate has touched upon the question of whether diseases can be understood as dysfunctional mechanisms or whether there are "pathological" mechanisms that deserve to be investigated and explained independently (Nervi 2010; Moghaddam-Taaheri 2011). Here I suggest that both views tell us something important about disease but that in many ins...

Regulatory T cells (Treg) have recently been identified as playing a central role in the immune response to allergens and during allergen-specific immunotherapy. We have extended our previous mathematical model describing the nonlinear dynamics of Th1-Th2 regulation by including Treg cells and their major cytokines. We hypothesize that immunotherap...