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1.
Wiley Interdiscip Rev RNA ; 14(2): e1752, 2023 03.
Article in English | MEDLINE | ID: mdl-35899407

ABSTRACT

Transcription factors (TFs) are present in all life forms and conserved across great evolutionary distances in eukaryotes. From yeast to complex multicellular organisms, they are pivotal players of cell fate decision by orchestrating gene expression at diverse molecular layers. Notably, TFs fine-tune gene expression by coordinating RNA fate at both the expression and splicing levels. They regulate alternative splicing, an essential mechanism for cell plasticity, allowing the production of many mRNA and protein isoforms in precise cell and tissue contexts. Despite this apparent role in splicing, how TFs integrate transcription and splicing to ultimately orchestrate diverse cell functions and cell fate decisions remains puzzling. We depict substantial studies in various model organisms underlining the key role of TFs in alternative splicing for promoting tissue-specific functions and cell fate. Furthermore, we emphasize recent advances describing the molecular link between the transcriptional and splicing activities of TFs. As TFs can bind both DNA and/or RNA to regulate transcription and splicing, we further discuss their flexibility and compatibility for DNA and RNA substrates. Finally, we propose several models integrating transcription and splicing activities of TFs in the coordination and diversification of cell and tissue identities. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Processing > Splicing Mechanisms.


Subject(s)
Cell Differentiation , Cell Lineage , RNA Splicing , Transcription Factors , Transcription, Genetic , Cell Differentiation/genetics , RNA Splicing/genetics , Transcription Factors/metabolism , Cell Lineage/genetics , Spatio-Temporal Analysis , DNA Polymerase II/chemistry , DNA Polymerase II/metabolism , DNA/metabolism , RNA/metabolism , Humans , Animals
2.
Nat Commun ; 13(1): 5037, 2022 08 26.
Article in English | MEDLINE | ID: mdl-36028502

ABSTRACT

Hox proteins have similar binding specificities in vitro, yet they control different morphologies in vivo. This paradox has been partially solved with the identification of Hox low-affinity binding sites. However, anterior Hox proteins are more promiscuous than posterior Hox proteins, raising the question how anterior Hox proteins achieve specificity. We use the AP2x enhancer, which is activated in the maxillary head segment by the Hox TF Deformed (Dfd). This enhancer lacks canonical Dfd-Exd sites but contains several predicted low-affinity sites. Unexpectedly, these sites are strongly bound by Dfd-Exd complexes and their conversion into optimal Dfd-Exd sites results only in a modest increase in binding strength. These small variations in affinity change the sensitivity of the enhancer to different Dfd levels, resulting in perturbed AP-2 expression and maxillary morphogenesis. Thus, Hox-regulated morphogenesis seems to result from the co-evolution of Hox binding affinity and Hox dosage for precise target gene regulation.


Subject(s)
Drosophila Proteins , Transcription Factors , Binding Sites , Gene Expression Regulation , Gene Expression Regulation, Developmental , Genes, Homeobox , Homeodomain Proteins
3.
Nucleic Acids Res ; 50(2): 763-783, 2022 01 25.
Article in English | MEDLINE | ID: mdl-34931250

ABSTRACT

Transcription factors (TFs) play a pivotal role in cell fate decision by coordinating gene expression programs. Although most TFs act at the DNA layer, few TFs bind RNA and modulate splicing. Yet, the mechanistic cues underlying TFs activity in splicing remain elusive. Focusing on the Drosophila Hox TF Ultrabithorax (Ubx), our work shed light on a novel layer of Ubx function at the RNA level. Transcriptome and genome-wide binding profiles in embryonic mesoderm and Drosophila cells indicate that Ubx regulates mRNA expression and splicing to promote distinct outcomes in defined cellular contexts. Our results demonstrate a new RNA-binding ability of Ubx. We find that the N51 amino acid of the DNA-binding Homeodomain is non-essential for RNA interaction in vitro, but is required for RNA interaction in vivo and Ubx splicing activity. Moreover, mutation of the N51 amino acid weakens the interaction between Ubx and active RNA Polymerase II (Pol II). Our results reveal that Ubx regulates elongation-coupled splicing, which could be coordinated by a dynamic interplay with active Pol II on chromatin. Overall, our work uncovered a novel role of the Hox TFs at the mRNA regulatory layer. This could be an essential function for other classes of TFs to control cell diversity.


Subject(s)
Drosophila Proteins/metabolism , Homeodomain Proteins/metabolism , RNA Polymerase II/metabolism , RNA Splicing , RNA/genetics , RNA/metabolism , Transcription Factors/metabolism , Amino Acids , Animals , Binding Sites , Chromatin Immunoprecipitation Sequencing , Drosophila Proteins/genetics , Drosophila melanogaster , Gene Expression Regulation , Models, Biological , Organ Specificity/genetics , Protein Binding , Protein Interaction Domains and Motifs , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA-Binding Proteins/metabolism , RNA-Seq
4.
J Cell Sci ; 133(18)2020 09 23.
Article in English | MEDLINE | ID: mdl-32878938

ABSTRACT

Hox proteins are major regulators of embryonic development, acting in the nucleus to regulate the expression of their numerous downstream target genes. By analyzing deletion forms of the Drosophila Hox protein Ultrabithorax (Ubx), we identified the presence of an unconventional nuclear export signal (NES) that overlaps with a highly conserved motif originally described as mediating the interaction with the PBC proteins, a generic and crucial class of Hox transcriptional cofactors that act in development and cancer. We show that this unconventional NES is involved in the interaction with the major exportin protein CRM1 (also known as Embargoed in flies) in vivo and in vitro We find that this interaction is tightly regulated in the Drosophila fat body to control the autophagy-repressive activity of Ubx during larval development. The role of the PBC interaction motif as part of an unconventional NES was also uncovered in other Drosophila and human Hox proteins, highlighting the evolutionary conservation of this novel function. Together, our results reveal the extreme molecular versatility of a unique short peptide motif for controlling the context-dependent activity of Hox proteins both at transcriptional and non-transcriptional levels.


Subject(s)
Drosophila Proteins , Drosophila , Active Transport, Cell Nucleus , Animals , Autophagy/genetics , Drosophila/genetics , Drosophila/metabolism , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Fat Body/metabolism , Gene Expression Regulation, Developmental , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Peptides , Transcription Factors/metabolism
5.
Mol Syst Biol ; 16(5): e9497, 2020 05.
Article in English | MEDLINE | ID: mdl-32430985

ABSTRACT

Studying the spatiotemporal control of gene regulatory networks at the single-cell level is still a challenge, yet it is key to understanding the mechanisms driving cellular identity. In their recent study, Aerts and colleagues (González-Blas et al, 2020) develop a new strategy to spatially map and integrate single-cell transcriptome and epigenome profiles in the Drosophila eye-antennal disc and to deduce in each cell precise enhancer-to-gene activity relationships. This opens a new era in the transcriptional regulation field, as it allows extracting from each of the thousands of cells forming a tissue the critical features driving their identity, from enhancer sequences to transcription factors to gene regulatory networks.


Subject(s)
Epigenomics , Transcriptome , Animals , Computational Biology , Gene Regulatory Networks , Genomics
6.
Nat Commun ; 11(1): 1388, 2020 03 13.
Article in English | MEDLINE | ID: mdl-32170121

ABSTRACT

Transcription factors (TFs) control cell fates by precisely orchestrating gene expression. However, how individual TFs promote transcriptional diversity remains unclear. Here, we use the Hox TF Ultrabithorax (Ubx) as a model to explore how a single TF specifies multiple cell types. Using proximity-dependent Biotin IDentification in Drosophila, we identify Ubx interactomes in three embryonic tissues. We find that Ubx interacts with largely non-overlapping sets of proteins with few having tissue-specific RNA expression. Instead most interactors are active in many cell types, controlling gene expression from chromatin regulation to the initiation of translation. Genetic interaction assays in vivo confirm that they act strictly lineage- and process-specific. Thus, functional specificity of Ubx seems to play out at several regulatory levels and to result from the controlled restriction of the interaction potential by the cellular environment. Thereby, it challenges long-standing assumptions such as differential RNA expression as determinant for protein complexes.


Subject(s)
Cell Lineage/physiology , Drosophila Proteins/metabolism , Drosophila/embryology , Drosophila/metabolism , Homeodomain Proteins/metabolism , Transcription Factors/metabolism , Animals , Chromatin/metabolism , Drosophila/genetics , Drosophila Proteins/genetics , Female , Gene Expression Regulation, Developmental , Genes, Insect , Homeodomain Proteins/genetics , Male , Mesoderm/cytology , Mesoderm/metabolism , Protein Interaction Domains and Motifs , Protein Interaction Maps , RNA/metabolism , Transcription Factors/genetics
7.
Elife ; 82019 05 03.
Article in English | MEDLINE | ID: mdl-31050646

ABSTRACT

During development cells become restricted in their differentiation potential by repressing alternative cell fates, and the Polycomb complex plays a crucial role in this process. However, how alternative fate genes are lineage-specifically silenced is unclear. We studied Ultrabithorax (Ubx), a multi-lineage transcription factor of the Hox class, in two tissue lineages using sorted nuclei and interfered with Ubx in mesodermal cells. We find that depletion of Ubx leads to the de-repression of genes normally expressed in other lineages. Ubx silences expression of alternative fate genes by retaining the Polycomb Group protein Pleiohomeotic at Ubx targeted genomic regions, thereby stabilizing repressive chromatin marks in a lineage-dependent manner. Our study demonstrates that Ubx stabilizes lineage choice by suppressing the multipotency encoded in the genome via its interaction with Pho. This mechanism may explain why the Hox code is maintained throughout the lifecycle, since it could set a block to transdifferentiation in adult cells.


Subject(s)
Cell Plasticity , Drosophila Proteins/metabolism , Drosophila/physiology , Gene Expression Regulation, Developmental , Homeodomain Proteins/metabolism , Transcription Factors/metabolism , Animals , Drosophila Proteins/deficiency , Gene Knockdown Techniques , Polycomb-Group Proteins/metabolism , Transcription Factors/deficiency
8.
Sci Rep ; 8(1): 10041, 2018 07 03.
Article in English | MEDLINE | ID: mdl-29968728

ABSTRACT

Lysine-specific demethylase 1 (LSD1) exerts dual effects on histone H3, promoting transcriptional repression via Lys4 (H3K4) demethylation or transcriptional activation through Lys9 (H3K9) demethylation. These activities are often exerted at transcriptional start sites (TSSs) and depend on the type of enhancer-bound transcription factor (TFs) with which LSD1 interacts. In particular, the Estrogen-Receptor Related α (ERRα) TF interacts with LSD1 and switches its activities toward H3K9 demethylation, resulting in transcriptional activation of a set of common target genes. However, how are the LSD1-TF and, in particular LSD1-ERRα, complexes determined to act at TSSs is not understood. Here we show that promoter-bound nuclear respiratory factor 1 (NRF1), but not ERRα, is essential to LSD1 recruitment at the TSSs of positive LSD1-ERRα targets. In contrast to ERRα, NRF1 does not impact on the nature of LSD1 enzymatic activity. We propose a three factor model, in which the LSD1 histone modifier requires a TSS tethering factor (NRF1) as well as an activity inducer (ERRα) to transcriptionally activate common targets. The relevance of this common network is illustrated by functional data, showing that all three factors are required for cell invasion in an MMP1 (Matrix MetalloProtease 1)-dependent manner, the expression of which is regulated by NRF1/LSD1/ERRα-mediated H3K9me2 demethylation.


Subject(s)
Histone Demethylases/metabolism , Nuclear Respiratory Factor 1/metabolism , Receptors, Estrogen/metabolism , Cell Line , Chromatin/metabolism , Gene Expression , Gene Expression Regulation , HEK293 Cells , Histones/metabolism , Humans , Promoter Regions, Genetic , Transcription Factors/metabolism , Transcription Initiation Site , Transcription, Genetic , Transcriptional Activation , ERRalpha Estrogen-Related Receptor
9.
Int J Dev Biol ; 62(11-12): 723-732, 2018.
Article in English | MEDLINE | ID: mdl-30604842

ABSTRACT

Hox transcription factors (TFs) function as key determinants in the specification of cell fates during development. They do so by triggering entire morphogenetic cascades through the activation of specific target genes. In contrast to their fundamental role in development, the molecular mechanisms employed by Hox TFs are still poorly understood. In recent years, a new picture has emerged regarding the function of Hox proteins in gene regulation. Initial studies have primarily focused on understanding how Hox TFs recognize and bind specific enhancers to activate defined Hox targets. However, genome-wide studies on the interactions and dynamics of Hox proteins have revealed a more elaborate function of the Hox factors. It is now known that Hox proteins are involved in several steps of gene expression with potential regulatory functions in the modification of the chromatin landscape and its accessibility, recognition and activation of specific cis-regulatory modules, assembly and activation of promoter transcription complexes and mRNA processing. In the coming years, the characterization of the molecular activity of Hox TFs in these mechanisms will greatly contribute to our general understanding of Hox activity.


Subject(s)
Gene Expression Regulation, Developmental , Genes, Homeobox , Promoter Regions, Genetic , Transcription Factors/genetics , Animals , Chromatin/genetics
10.
PLoS One ; 12(11): e0188871, 2017.
Article in English | MEDLINE | ID: mdl-29190800

ABSTRACT

The LSD1 histone demethylase is highly expressed in breast tumors where it constitutes a factor of poor prognosis and promotes traits of cancer aggressiveness such as cell invasiveness. Recent work has shown that the Estrogen-Related Receptor α (ERRα) induces LSD1 to demethylate the Lys 9 of histone H3. This results in the transcriptional activation of a number of common target genes, several of which being involved in cellular invasion. High expression of ERRα protein is also a factor of poor prognosis in breast tumors. Here we show that, independently of its demethylase activities, LSD1 protects ERRα from ubiquitination, resulting in overexpression of the latter protein. Our data also suggests that the elevation of LSD1 mRNA and protein in breast cancer (as compared to normal tissue) may be a key event to increase ERRα protein, independently of its corresponding mRNA.


Subject(s)
Breast Neoplasms/genetics , Histone Demethylases/metabolism , Receptors, Estrogen/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Demethylation , Female , Histone Demethylases/genetics , Humans , Receptors, Estrogen/genetics , ERRalpha Estrogen-Related Receptor
11.
Proc Natl Acad Sci U S A ; 114(15): 3909-3914, 2017 04 11.
Article in English | MEDLINE | ID: mdl-28348226

ABSTRACT

Lysine Specific Demethylase 1 (LSD1) removes mono- and dimethyl groups from lysine 4 of histone H3 (H3K4) or H3K9, resulting in repressive or activating (respectively) transcriptional histone marks. The mechanisms that control the balance between these two antagonist activities are not understood. We here show that LSD1 and the orphan nuclear receptor estrogen-related receptor α (ERRα) display commonly activated genes. Transcriptional activation by LSD1 and ERRα involves H3K9 demethylation at the transcriptional start site (TSS). Strikingly, ERRα is sufficient to induce LSD1 to demethylate H3K9 in vitro. The relevance of this mechanism is highlighted by functional data. LSD1 and ERRα coregulate several target genes involved in cell migration, including the MMP1 matrix metallo-protease, also activated through H3K9 demethylation at the TSS. Depletion of LSD1 or ERRα reduces the cellular capacity to invade the extracellular matrix, a phenomenon that is rescued by MMP1 reexpression. Altogether our results identify a regulatory network involving a direct switch in the biochemical activities of a histone demethylase, leading to increased cell invasion.


Subject(s)
Histone Demethylases/metabolism , Histones/metabolism , Receptors, Estrogen/metabolism , Cell Movement , Gene Expression Regulation , HEK293 Cells , Histone Demethylases/genetics , Humans , Lysine/metabolism , Matrix Metalloproteinase 1/metabolism , Methylation , Promoter Regions, Genetic , Receptors, Estrogen/genetics , Transcription Initiation Site , ERRalpha Estrogen-Related Receptor
12.
Mol Cell Endocrinol ; 432: 37-43, 2016 09 05.
Article in English | MEDLINE | ID: mdl-26206717

ABSTRACT

Bone loss is naturally occurring in aging males and females and exacerbated in the latter after menopause, altogether leading to cumulative skeleton fragility and increased fracture risk. Two types of therapeutic strategies can be envisioned to counteract age- or menopause-associated bone loss, aiming at either reducing bone resorption exerted by osteoclasts or, alternatively, promoting bone formation by osteoblasts. We here summarize data suggesting that inhibition of the Estrogen-Related Receptors α and/or γ could promote bone formation and compensate for bone loss induced by ageing or estrogen-deficiency.


Subject(s)
Bone and Bones/cytology , Cell Lineage , Receptors, Estrogen/metabolism , Animals , Humans , Mesoderm/cytology , Models, Biological , Receptors, Cytoplasmic and Nuclear/metabolism , ERRalpha Estrogen-Related Receptor
13.
PLoS One ; 10(3): e0120672, 2015.
Article in English | MEDLINE | ID: mdl-25781607

ABSTRACT

The post-menopausal decrease in estrogen circulating levels results in rapid skin deterioration pointing out to a protective effect exerted by these hormones. The identity of the skin cell type responding to estrogens is unclear as are the cellular and molecular processes they elicit. Here, we reported that lack of estrogens induces rapid re-organization of the human dermal fibroblast cytoskeleton resulting in striking cell shape change. This morphological change was accompanied by a spatial re-organization of focal adhesion and a substantial reduction of their number as evidenced by vinculin and actin co-staining. Cell morphology and cytoskeleton organization was fully restored upon 17ß-estradiol (E2) addition. Treatment with specific ER antagonists and cycloheximide respectively showed that the E2 acts independently of the classical Estrogen Receptors and that cell shape change is mediated by non-genomic mechanisms. E2 treatment resulted in a rapid and transient activation of ERK1/2 but not Src or PI3K. We show that human fibroblasts express the non-classical E2 receptor GPR30 and that its agonist G-1 phenocopies the effect of E2. Inhibiting GPR30 through treatment with the G-15 antagonist or specific shRNA impaired E2 effects. Altogether, our data reveal a novel mechanism by which estrogens act on skin fibroblast by regulating cell shape through the non-classical G protein-coupled receptor GPR30 and ERK1/2 activation.


Subject(s)
Estradiol/pharmacology , Estrogens/pharmacology , Fibroblasts/metabolism , MAP Kinase Signaling System/drug effects , Receptors, Estrogen/metabolism , Receptors, G-Protein-Coupled/metabolism , Adult , Benzodioxoles/pharmacology , Dermis , Estrogen Receptor beta/metabolism , Female , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Quinolines/pharmacology , Receptors, Estrogen/antagonists & inhibitors , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/antagonists & inhibitors
14.
Proc Natl Acad Sci U S A ; 111(42): 15108-13, 2014 Oct 21.
Article in English | MEDLINE | ID: mdl-25288732

ABSTRACT

Several physiopathological processes require orientated cellular migration. This phenomenon highly depends on members of the RHO family of GTPases. Both excessive and deficient RHO activity impair directional migration. A tight control is thus exerted on these proteins through the regulation of their activation and of their stability. Here we show that the estrogen-related receptor α (ERRα) directly activates the expression of TNFAIP1, the product of which [BTB/POZ domain-containing adapter for Cullin3-mediated RhoA degradation 2 (BACURD2)] regulates RHOA protein turnover. Inactivation of the receptor leads to enhanced RHOA stability and activation. This results in cell disorientation, increased actin network, and inability to form a lamellipodium at the migration edge. As a consequence, directional migration, but not cell motility per se, is impaired in the absence of the receptor, under pathological as well as physiological conditions. Altogether, our results show that the control exerted by ERRα on RHOA stability is required for directional migration.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cell Movement , Receptors, Estrogen/metabolism , rhoA GTP-Binding Protein/metabolism , Actins/metabolism , Animals , Cell Line, Tumor , Cullin Proteins/metabolism , Extracellular Matrix/metabolism , Humans , Macrophages/cytology , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Neoplasm Invasiveness , Neoplasm Metastasis , Prognosis , Protein Stability , Protein Structure, Tertiary , Proteins/metabolism , Wound Healing , ERRalpha Estrogen-Related Receptor
15.
PLoS One ; 8(1): e54837, 2013.
Article in English | MEDLINE | ID: mdl-23359549

ABSTRACT

ERRα is an orphan member of the nuclear receptor family, the complete inactivation of which confers resistance to bone loss induced by ageing and estrogen withdrawal to female mice in correlation with increased bone formation in vivo. Furthermore ERRα negatively regulates the commitment of mesenchymal cells to the osteoblast lineage ex vivo as well as later steps of osteoblast maturation. We searched to determine whether the activities of ERRα on osteoblast maturation are responsible for one or both types of in vivo induced bone loss. To this end we have generated conditional knock out mice in which the receptor is normally present during early osteoblast differentiation but inactivated upon osteoblast maturation. Bone ageing in these animals was similar to that observed for control animals. In contrast conditional ERRαKO mice were completely resistant to bone loss induced by ovariectomy. We conclude that the late (maturation), but not early (commitment), negative effects of ERRα on the osteoblast lineage contribute to the reduced bone mineral density observed upon estrogen deficiency.


Subject(s)
Estrogen Receptor alpha/physiology , Estrogens/deficiency , Osteoblasts/cytology , Osteoporosis/physiopathology , Animals , Cell Lineage , Estrogen Receptor alpha/genetics , Male , Mice , Mice, Knockout , Mice, Transgenic , Osteoporosis/pathology , Rabbits
16.
Horm Mol Biol Clin Investig ; 14(3): 107-12, 2013 Aug.
Article in English | MEDLINE | ID: mdl-25436725

ABSTRACT

The estrogen-related receptors (ERRα, ß, and γ) are orphan members of the nuclear receptor superfamily. ERRα and γ are highly expressed in tissues displaying elevated energy demands and are involved in several aspects of energetic metabolism, which they regulate mostly in association with members of the PGC-1 coactivator family. These activities have mostly been documented in the liver, heart, or skeletal muscle. ERRα and γ are also highly expressed in adipocytes. Their precise roles in this cell type are less documented, although published data indicate that they contribute to cell differentiation as well as functionality. This review describes these activities.


Subject(s)
Adipocytes/metabolism , Receptors, Estrogen/metabolism , Animals , Cell Differentiation , Humans
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