Publications
23 results found
Amblard I, Baranasic D, Moyon B, et al., 2024, A dual enhancer-silencer element ensures transient Cdx2 expression during posterior body formation
During development, cells express precise gene expression programmes to assemble the trunk of the body plan. Appropriate control over the duration of the transcription factor Cdx2 is critical to achieve this outcome, yet, how cells control the onset, maintenance or termination of Cdx2, has remained unclear. Here, we delineate the cis-regulatory logic orchestrating dynamic Cdx2 expression in mouse caudal epiblast progenitors and their derivatives - spinal cord and presomitic mesoderm. Combining CRISPR-mediated deletion of regulatory elements with in vitro models and in vivo validation, we demonstrate that distinct enhancers, and a silencer, embedded at the Cdx2 locus, act sequentially to drive transient Cdx2 expression. We pinpoint a minimal silencer element that relies on a nuclear receptor motif to extinguish Cdx2. Changing this single motif converts the repressive element to an enhancer with opposite regulatory behaviour. Our findings elucidate design principles of developmental enhancers and silencers and establish a dual enhancer-silencer cis-regulatory logic ensuring precise spatiotemporal control over gene expression for vertebrate body patterning.
Semprich C, Davidson L, Torres AA, et al., 2022, ERK1/2 signalling dynamics promote neural differentiation by regulating chromatin accessibility and the polycomb repressive complex, PLOS BIOLOGY, Vol: 20, ISSN: 1544-9173
- Author Web Link
- Cite
- Citations: 2
Needham J, Metzis V, 2022, Heads or tails: making the spinal cord, DEVELOPMENTAL BIOLOGY, Vol: 485, Pages: 80-92, ISSN: 0012-1606
- Author Web Link
- Cite
- Citations: 1
Blassberg R, Patel H, Watson T, et al., 2022, Sox2 levels regulate the chromatin occupancy of WNT mediators in epiblast progenitors responsible for vertebrate body formation, NATURE CELL BIOLOGY, Vol: 24, Pages: 633-+, ISSN: 1465-7392
- Author Web Link
- Cite
- Citations: 15
Binagui-Casas A, Dias A, Guillot C, et al., 2021, Building consensus in neuromesodermal research: Current advances and future biomedical perspectives, CURRENT OPINION IN CELL BIOLOGY, Vol: 73, Pages: 133-140, ISSN: 0955-0674
- Author Web Link
- Cite
- Citations: 11
Exelby K, Herrera-Delgado E, Perez LG, et al., 2021, Precision of tissue patterning is controlled by dynamical properties of gene regulatory networks, DEVELOPMENT, Vol: 148, ISSN: 0950-1991
- Author Web Link
- Cite
- Citations: 20
Blassberg R, Patel H, Watson T, et al., 2020, Sox2 levels configure the WNT response of epiblast progenitors responsible for vertebrate body formation
<jats:title>Abstract</jats:title><jats:p>WNT signalling has multiple roles. It maintains pluripotency of embryonic stem cells, assigns posterior identity in the epiblast and induces mesodermal tissue. We provide evidence that these distinct functions are conducted by the transcription factor SOX2, which adopts different modes of chromatin interaction and regulatory element selection depending on its level of expression. At high levels, SOX2 acts as a pioneer factor, displacing nucleosomes from regulatory elements with high affinity SOX2 binding sites and recruiting the WNT effector, TCF/β-catenin, to maintain pluripotent gene expression. Reducing SOX2 levels destabilises pluripotency and reconfigures SOX2/TCF/β-catenin occupancy to caudal epiblast expressed genes. These contain low-affinity SOX2 sites and are co-occupied by T/Bra and CDX. The loss of SOX2 allows WNT induced mesodermal differentiation. These findings define a role for Sox2 levels in dictating the chromatin occupancy of TCF/β-catenin and reveal how context specific responses to a signal are configured by the level of a transcription factor.</jats:p>
Exelby K, Herrera-Delgado E, Perez LG, et al., 2019, Precision of Tissue Patterning is Controlled by Dynamical Properties of Gene Regulatory Networks
<jats:title>Abstract</jats:title><jats:p>During development, gene regulatory networks allocate cell fates by partitioning tissues into spatially organised domains of gene expression. How the sharp boundaries that delineate these gene expression patterns arise, despite the stochasticity associated with gene regulation, is poorly understood. We show, in the vertebrate neural tube, using perturbations of coding and regulatory regions, that the structure of the regulatory network contributes to boundary precision. This is achieved, not by reducing noise in individual genes, but by the configuration of the network modulating the ability of stochastic fluctuations to initiate gene expression changes. We use a computational screen to identify network properties that influence boundary precision, revealing two dynamical mechanisms by which small gene circuits attenuate the effect of noise in order to increase patterning precision. These results highlight design principles of gene regulatory networks that produce precise patterns of gene expression.</jats:p>
Semprich CI, Metzis V, Patel H, et al., 2019, ERK1/2 signalling dynamics promote neural differentiation by regulating the polycomb repressive complex
<jats:title>Abstract</jats:title><jats:p>Fibroblast Growth Factor (FGF) is a neural inducer in many vertebrate embryos, but how it regulates chromatin organization to coordinate the activation of neural genes is unclear. Moreover, for differentiation to progress FGF signalling has to decline. Why this signalling dynamic is required has not been determined. Here we show that dephosphorylation of the FGF effector kinase ERK1/2 rapidly increases chromatin accessibility at neural genes in mouse embryos and, using ATAC-seq in human embryonic stem cell derived spinal cord precursors, we demonstrate that this occurs across hundreds of neural genes. Importantly, while Erk1/2 inhibition induces precocious neural gene transcription, this step involves dissociation of the polycomb repressive complex from gene loci and takes places independently of subsequent loss of the repressive histone mark H3K27me3 and transcriptional onset. We find that loss of ERK1/2 activity but not its occupancy at neural genes is critical for this mechanism. Moreover, transient ERK1/2 inhibition is sufficient for polycomb protein dissociation and this is not reversed on resumption of ERK1/2 signalling. These data indicate that ERK1/2 signalling maintains polycomb repressive complexes at neural genes, that its decline coordinates their increased accessibility and that this is a directional molecular mechanism, which initiates the process of neural commitment. Furthermore, as the polycomb repressive complexes repress but also ready genes for transcription, these findings suggest that ERK1/2 promotion of these complexes is a rite of passage for subsequent differentiation.</jats:p>
Gabrysova L, Alvarez-Martinez M, Luisier R, et al., 2019, c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4(+) T cells (vol 19, pg 497, 2018), NATURE IMMUNOLOGY, Vol: 20, Pages: 374-374, ISSN: 1529-2908
Metzis V, Steinhauser S, Pakanavicius E, et al., 2018, Regionalization of the nervous system requires axial allocation prior to neural lineage commitment, Cell, Vol: 175, Pages: 1105-1118.E17, ISSN: 0092-8674
Neural induction in vertebrates generates a central nervous system that extends the rostral-caudal length of the body. The prevailing view is that neural cells are initially induced with anterior (forebrain) identity, with caudalising signals then converting a proportion to posterior fates (spinal cord). To test this model, we used chromatin accessibility assays to define how cells adopt region-specific neural fates. Together with genetic and biochemical perturbations this identified a developmental time window in which genome-wide chromatin remodeling events preconfigure epiblast cells for neural induction. Contrary to the established model, this revealed that cells commit to a regional identity before acquiring neural identity. This “primary regionalization” allocates cells to anterior or posterior regions of the nervous system, explaining how cranial and spinal neurons are generated at appropriate axial positions. These findings prompt a revision to models of neural induction and support the proposed dual evolutionary origin of the vertebrate central nervous system.
Metzis V, Steinhauser S, Pakanavicius E, et al., 2018, Nervous system regionalization entails axial allocation before neural differentiation, Cell, Vol: 175, Pages: 1105-1118.e17, ISSN: 0092-8674
Neural induction in vertebrates generates a CNS that extends the rostral-caudal length of the body. The prevailing view is that neural cells are initially induced with anterior (forebrain) identity; caudalizing signals then convert a proportion to posterior fates (spinal cord). To test this model, we used chromatin accessibility to define how cells adopt region-specific neural fates. Together with genetic and biochemical perturbations, this identified a developmental time window in which genome-wide chromatin-remodeling events preconfigure epiblast cells for neural induction. Contrary to the established model, this revealed that cells commit to a regional identity before acquiring neural identity. This “primary regionalization” allocates cells to anterior or posterior regions of the nervous system, explaining how cranial and spinal neurons are generated at appropriate axial positions. These findings prompt a revision to models of neural induction and support the proposed dual evolutionary origin of the vertebrate CNS.
Gabrysova L, Alvarez-Martinez M, Luisier R, et al., 2018, c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4(+) T cells, Nature Immunology, Vol: 19, Pages: 497-507, ISSN: 1529-2908
The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4+ T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4+ T cells in disease models involving the TH1 subset of helper T cells (malaria), TH2 cells (allergy) and TH17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in TH1 and TH2 responses, TH17 cell–mediated pathology was reduced in this context, with an accompanying decrease in TH17 cells and increase in Foxp3+ regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor RORγt (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.
Lu H, Galeano MCR, Ott E, et al., 2017, Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease, Nature Genetics, Vol: 49, Pages: 1025-1034, ISSN: 1061-4036
Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. In agreement with a defect in the diffusion barrier, we found that the ciliary-membrane translocation of the PKD proteins polycystin-1 and polycystin-2 is compromised in DZIP1L-mutant cells. Together, these data provide what is, to our knowledge, the first conclusive evidence that ARPKD is not a homogeneous disorder and further establish DZIP1L as a second gene involved in ARPKD pathogenesis.
Exelby K, Herrera E, Metzis V, et al., 2017, Boundary precision in the ventral neural tube, 18th International Congress of Developmental Biology, Publisher: ELSEVIER SCIENCE BV, Pages: S74-S74, ISSN: 0925-4773
Cortes CR, Metzis V, Wicking C, 2015, Unmasking the ciliopathies: craniofacial defects and the primary cilium, WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY, Vol: 4, Pages: 637-653, ISSN: 1759-7684
- Author Web Link
- Cite
- Citations: 29
Gouti M, Metzis V, Briscoe J, 2015, The route to spinal cord cell types: a tale of signals and switches, TRENDS IN GENETICS, Vol: 31, Pages: 282-289, ISSN: 0168-9525
- Author Web Link
- Cite
- Citations: 68
Metzis V, Courtney AD, Kerr MC, et al., 2013, Patched1 is required in neural crest cells for the prevention of orofacial clefts, HUMAN MOLECULAR GENETICS, Vol: 22, Pages: 5026-5035, ISSN: 0964-6906
- Author Web Link
- Cite
- Citations: 31
Metzis V, Courtney A, Ferguson C, et al., 2011, Patched1 is essential for nasal pit invagination in mouse, 70th Annual Meeting of the Society-for-Developmental-Biology, Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE, Pages: 148-148, ISSN: 0012-1606
Bruce SJ, Butterfield NC, Metzis V, et al., 2010, Inactivation of <i>Patched1</i> in the Mouse Limb Has Novel Inhibitory Effects on the Chondrogenic Program, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 285, Pages: 27967-27981
- Author Web Link
- Cite
- Citations: 29
Town L, McGlinn E, Fiorenza S, et al., 2009, The Metalloendopeptidase Gene <i>Pitrm1</i> Is Regulated by Hedgehog Signaling in the Developing Mouse Limb and Is Expressed in Muscle Progenitors, DEVELOPMENTAL DYNAMICS, Vol: 238, Pages: 3175-3184, ISSN: 1058-8388
- Author Web Link
- Cite
- Citations: 12
Butterfield NC, Metzis V, McGlinn E, et al., 2009, Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb, DEVELOPMENT, Vol: 136, Pages: 3515-3524, ISSN: 0950-1991
- Author Web Link
- Cite
- Citations: 48
McGlinn E, Richman JM, Metzis V, et al., 2008, Expression of the NET family member <i>Zfp503</i> is regulated by hedgehog and BMP signaling in the limb, DEVELOPMENTAL DYNAMICS, Vol: 237, Pages: 1172-1182, ISSN: 1058-8388
- Author Web Link
- Cite
- Citations: 17
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.