Biology subjects

Gronemeyer, H.

Publications and source records attributed to Gronemeyer, H..

4 recordsLinked to original sources

bioRxiv2022

A synergistic activation of RARb and RARg nuclear receptors restores cell-types specialization during stem cells differentiation by hijacking RARa-controlled program

How cells respond to different external cues to develop along defined cell lineages to form complex tissues is a major question in systems biology. Here, we investigated the potential of retinoic acid receptor (RARs)-selective synthetic agonists to activate the gene-regulatory programs driving cell specialization during nervous tissue formation from P19 stem cells. Specifically, we found that the synergistic activation of the RAR{beta} and RAR{gamma} by selective ligands (BMS641 or BMS961) induces cell maturation to specialized neuronal subtypes, as well as to astrocytes and oligodendrocyte precursors. Using RAR istoype knockout lines exposed to RAR-specific agonists, interrogated by global transcriptome landscaping and in silico modeling of transcription regulatory signal propagation, revealed major RAR-driven gene programs essential for optimal neuronal cell specialization, and hijacked by the synergistic activation of the RAR{beta} and RAR{gamma} receptors. Overall, this study provides a systems biology view of the gene programs accounting for the previously observed redundancy between RAR receptors, paving the way towards their potential use for directing cell specialization during nervous tissue formation.

molecular biology↗

bioRxiv2020

The comprehensive roadmaps of reprogramming and transformation unveiled antagonistic roles for bHLH transcription factors in the control of cellular plasticity

Coordinated changes of cellular identity and plasticity are critical for pluripotent reprogramming (PR) and malignant transformation (MT). However, the molecular circuitries orchestrating these modifications, as well as their degree of analogy during reprogramming and transformation, remain unknown. To address this question, we generated "repro-transformable" mice models and dissected comparatively the early events underpinning PR - mediated by Oct4, Sox2, Klf4, c-Myc - and MT - triggered by oncogenic Ras and c-Myc. Transcriptomic analyses allowed the identification of a unique set of markers - the cell surface glycoprotein Thy1 and the transcription factor (TF) Bcl11b - that are commonly downregulated during PR and MT and delineate cellular intermediates (CI) highly amenable to generate pluripotent or malignant derivatives. Comprehensive transcriptomic, epigenomic and functional analyses of different CI, prone or refractory to PR/MT, unveiled that cellular plasticity acquisition precedes the broad extinction of cellular identity. It also demonstrated the existence of specific and shared molecular features of PR and MT while ensuring the identification of broad-range regulators of cellular plasticity. As a proof-of-concept, we revealed that the basic helix-loop-helix (bHLH) class A TF Atoh8 constrains rodent and human iPS cells generation as well as MT and direct neuron conversion. Mechanistically, this TF hampers the reactivation of the pluripotent network during PR and limits the acquisition of phenotypic plasticity during MT. Furthermore, an integrated analysis of Atoh8 genome-wide binding, alongside the other bHLH TFs c-Myc, Ascl1 and MyoD promoting reprogramming/transdifferentiation, unveiled how Atoh8 constrains cellular plasticity by occupying a specific subset of MEF enhancers and by finetuning WNT signalling activity. Collectively, by deconvoluting the early steps of the reprogramming and transformation roadmaps, this integrated study uncoupled changes of cellular plasticity and identity to shed light on novel insights into reprogramming and cancer biology. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/424606v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1718383org.highwire.dtl.DTLVardef@1714ab8org.highwire.dtl.DTLVardef@e0958borg.highwire.dtl.DTLVardef@7a0643_HPS_FORMAT_FIGEXP M_FIG C_FIG One-sentence summaryComparative roadmaps of cellular plasticity acquisition during pluripotent reprogramming and malignant transformation.

cell biology↗

bioRxiv2019

Patient-matched analysis identifies deregulated networks in prostate cancer to guide personalized therapeutic intervention

Prostate cancer (PrCa) is the second most common malignancy in men1. More than 50% of advanced prostate cancers display the TMPRSS2-ERG fusion2. Despite extensive cancer genome/transcriptome2-4 and phosphoproteome5 data, little is known about the impact of mutations and altered transcription on regulatory networks in the PrCa of individual patients. Using patient-matched normal and tumor samples, we established somatic variations and differential transcriptome profiles of primary ERG-positive prostate cancers. Integration of protein-protein interaction and gene-regulatory network databases6, 7 defined highly diverse patient-specific network alterations. We found that different components of a given regulatory pathway were altered by novel and known mutations and/or aberrant gene expression, including deregulated ERG targets, such that different sets of pathways were altered in each individual PrCa. In a given PrCa, several deregulated pathways share common factors, predicting synergistic effects on cancer progression. Our integrated analysis provides a paradigm to identify key deregulated factors within regulatory networks to guide personalized therapies.

genomics↗

bioRxiv2018

Highly dynamic chromatin interactions drive neurogenesis through gene regulatory networks

Lineage commitment is a fundamental process that enables the morphogenesis of multicellular organisms from a single pluripotent cell. While many genes involved in the commitment to specific lineages are known, the logic of their joint action is incompletely understood, and predicting the effects of genetic perturbations on lineage commitment is still challenging. Here, we devised a gene regulatory network analysis approach, GRN-loop, to identify key cis-regulatory DNA elements and transcription factors that drive lineage commitment. GRN-loop is based on signal propagation and combines transcription factor binding data with the temporal profiles of gene expression, chromatin state and 3D chromosomal architecture. Applying GRN-loop to a model of morphogen-induced early neural lineage commitment, we discovered a set of driver transcription factors and enhancers, some of them validated in recent data and others hitherto unknown. Our work provides the basis for an integrated understanding of neural lineage commitment, and demonstrates the potential of gene regulatory network analyses informed by 3D chromatin architecture to uncover the key genes and regulatory elements driving developmental processes.

molecular biology↗