A5056945647- CRISPR and Genetic Engineering
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Pluripotent Stem Cells Research
- Genomics and Chromatin Dynamics
- Animal Genetics and Reproduction
- Cancer-related molecular mechanisms research
- RNA Research and Splicing
- Biomedical Ethics and Regulation
- Genetics, Aging, and Longevity in Model Organisms
- Renal and related cancers
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Plant Virus Research Studies
- RNA Interference and Gene Delivery
- Chromosomal and Genetic Variations
- Genetics and Neurodevelopmental Disorders
- Reproductive Biology and Fertility
- melanin and skin pigmentation
- Advanced Electron Microscopy Techniques and Applications
- PARP inhibition in cancer therapy
- Genomic variations and chromosomal abnormalities
- Immunodeficiency and Autoimmune Disorders
- Gene Regulatory Network Analysis
Max Planck Institute for Molecular Genetics
1980-2024
Institut Curie
2012-2017
Inserm
2013-2017
Centre National de la Recherche Scientifique
2013-2017
Max Planck Society
1980-2017
Google (United States)
2017
Université Paris Sciences et Lettres
2017
German Cancer Research Center
2009-2010
Heidelberg University
2010
Humboldt-Universität zu Berlin
2009-2010
Understanding how regulatory sequences interact in the context of chromosomal architecture is a central challenge biology. Chromosome conformation capture revealed that mammalian chromosomes possess rich hierarchy structural layers, from multi-megabase compartments to sub-megabase topologically associating domains (TADs) and sub-TAD contact domains. TADs appear act as microenvironments by constraining segregating interactions across discrete regions. However, it unclear whether other (or...
Abstract Certain cellular processes are dose-dependent, requiring specific quantities or stoichiometries of gene products, as exemplified by haploinsufficiency and sex-chromosome dosage compensation. Understanding dosage-sensitive requires tools to quantitatively modulate protein abundance. Here we present CasTuner, a CRISPR-based toolkit for analog tuning endogenous expression. The system exploits Cas-derived repressors that tuned ligand titration through FKBP12 F36V degron domain. CasTuner...
Although cell‐to‐cell variability has been recognized as an unavoidable consequence of stochasticity in gene expression, it may also serve a functional role for tuning physiological responses within cell population. In the immune system, remarkably large expression cytokine genes observed homogeneous populations lymphocytes, but underlying molecular mechanisms are incompletely understood. Here, we study interleukin‐4 ( il4 ) T‐helper combining mathematical modeling with experimental...
To initiate X-Chromosome inactivation (XCI), the long noncoding RNA Xist mediates chromosome-wide gene silencing of one X Chromosome in female mammals to equalize dosage between sexes. The efficiency is highly variable across genes, with some genes even escaping XCI somatic cells. A gene's susceptibility Xist-mediated appears be determined by a complex interplay epigenetic and genomic features; however, underlying rules remain poorly understood. We have quantified kinetics at level nascent...
Abstract To ensure dosage compensation between the sexes, one randomly chosen X chromosome is silenced in each female cell process of X-chromosome inactivation (XCI). XCI initiated during early development through upregulation long non-coding RNA Xist, which mediates chromosome-wide gene silencing. Cell differentiation, Xist and silencing are thought to be coupled at multiple levels exactly out two chromosomes. Here we perform an integrated analysis all three processes allele-specific...
Abstract Background X-chromosomal genes contribute to sex differences, in particular during early development, when both X chromosomes are active females. Double X-dosage shifts female pluripotent cells towards the naive stem cell state by increasing pluripotency factor expression, inhibiting differentiation-promoting MAP kinase (MAPK) signaling pathway, and delaying differentiation. Results To identify genetic basis of these we use a two-step CRISPR screening approach comprehensively...
Developmental genes such as Xist, which initiates X chromosome inactivation, are controlled by complex cis-regulatory landscapes, decode multiple signals to establish specific spatiotemporal expression patterns. Xist integrates information on dosage and developmental stage trigger inactivation in the epiblast specifically female embryos. Through a pooled CRISPR screen differentiating mouse embryonic stem cells, we identify functional enhancer elements of at onset random inactivation....
Genomes are organised through hierarchical structures, ranging from local kilobase-scale cis-regulatory contacts to large chromosome territories. Most notably, (sub)-compartments partition chromosomes according transcriptional activity, while topologically associating domains (TADs) define landscapes. The inactive X in mammals has provided unique insights into the regulation and function of three-dimensional (3D) genome. Concurrent with silencing majority genes major alterations its...
Many mammals can temporally uncouple conception from parturition by pacing down their development around the blastocyst stage. In mice, this dormant state is achieved decreasing activity of growth-regulating mTOR signaling pathway. It unknown whether ability conserved in general and humans particular. Here, we show that pathway induces human pluripotent stem cells (hPSCs) blastoids to enter a with limited proliferation, developmental progression, capacity attach endometrial cells. These...
SUMMARY Many mammals can control the timing of gestation and birth by pausing embryonic development at blastocyst stage. It is unknown whether capacity to pause conserved, in general across mammals, more specifically humans. Activity growth regulating mTOR pathway governs developmental mouse ( 1 ). Here we show a stage-specific delay progression human via inhibition. In this context, blastoids pluripotent stem cells naïve naïve-like, but not primed, states be induced enter dormant state,...
The Hsp70 family of molecular chaperones acts to prevent protein misfolding, import proteins into organelles, unravel aggregates, and enhance cell survival under stress conditions. These activities are all mediated by recognition diverse hydrophobic sequences via a C-terminal substrate-binding domain. ATP-binding/hydrolysis the N-terminal ATPase domain regulates interconversion between low high affinity conformations. empty state has been difficult study because its propensity bind nearly...
Human pluripotent stem cells (hPSCs) are of fundamental relevance in regenerative medicine. Naïve hPSCs hold promise to overcome some the limitations conventional (primed) hPSCs, including recurrent epigenetic anomalies. Naïve-to-primed transition (capacitation) follows transcriptional dynamics human embryonic epiblast and is necessary for somatic differentiation from naïve hPSCs. We found that capacitated transcriptionally closer postimplantation than This prompted us comprehensively study...
Abstract X-chromosome inactivation (XCI) balances gene expression between the sexes in female mammals. Shortly after fertilization, upregulation of Xist RNA from one X chromosome initiates XCI, leading to chromosome-wide silencing. XCI is maintained all cell types, except germ line and pluripotent state where reversed. The mechanisms triggering have remained elusive. Here we identify GATA transcription factors as potent activators Xist. Through a pooled CRISPR activation screen murine...
ABSTRACT This Review elucidates the regulatory principles of random monoallelic expression by focusing on two well-studied examples: X-chromosome inactivation regulator Xist and olfactory receptor gene family. Although choice a single X chromosome or occurs in different developmental contexts, common guide both systems. In cases, an event breaks symmetry between genetically epigenetically identical copies gene, leading to one allele, stabilized through negative feedback control. many steps...