Chromatin organization and global regulation of<i>Hox</i>gene clusters

Montavon, Thomas; Duboule, Denis

doi:10.1098/rstb.2012.0367

Cited by 70 publications

(51 citation statements)

References 93 publications

(125 reference statements)

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“…2B). These progressive changes of chromatin accessibility/TF association and gain of marks for active transcription with concomitant loss of "repressive" marks correlated with the collinear mechanism for transcription activation of Hox genes, previously described in other systems (Kashyap et al 2011;Montavon and Duboule 2013).…”

Section: Ra Induces Both Common and Cell Fatespecific Programs In F9 supporting

confidence: 74%

Reconstructed cell fate–regulatory programs in stem cells reveal hierarchies and key factors of neurogenesis

Mendoza-Parra¹,

Malysheva²,

Saleem³

et al. 2016

Genome Res.

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Cell lineages, which shape the body architecture and specify cell functions, derive from the integration of a plethora of cell intrinsic and extrinsic signals. These signals trigger a multiplicity of decisions at several levels to modulate the activity of dynamic gene regulatory networks (GRNs), which ensure both general and cell-specific functions within a given lineage, thereby establishing cell fates. Significant knowledge about these events and the involved key drivers comes from homogeneous cell differentiation models. Even a single chemical trigger, such as the morphogen all-trans retinoic acid (RA), can induce the complex network of gene-regulatory decisions that matures a stem/precursor cell to a particular step within a given lineage. Here we have dissected the GRNs involved in the RA-induced neuronal or endodermal cell fate specification by integrating dynamic RXRA binding, chromatin accessibility, epigenetic promoter epigenetic status, and the transcriptional activity inferred from RNA polymerase II mapping and transcription profiling. Our data reveal how RA induces a network of transcription factors (TFs), which direct the temporal organization of cognate GRNs, thereby driving neuronal/endodermal cell fate specification. Modeling signal transduction propagation using the reconstructed GRNs indicated critical TFs for neuronal cell fate specification, which were confirmed by CRISPR/Cas9-mediated genome editing. Overall, this study demonstrates that a systems view of cell fate specification combined with computational signal transduction models provides the necessary insight in cellular plasticity for cell fate engineering. The present integrated approach can be used to monitor the in vitro capacity of (engineered) cells/tissues to establish cell lineages for regenerative medicine.

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Section: Ra Induces Both Common and Cell Fatespecific Programs In F9 supporting

confidence: 74%

Reconstructed cell fate–regulatory programs in stem cells reveal hierarchies and key factors of neurogenesis

Mendoza-Parra¹,

Malysheva²,

Saleem³

et al. 2016

Genome Res.

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“…The molecular mechanisms governing the development of mammalian limbs have been approached in mouse models through multiple levels of analysis, from chromatin dynamics, to enhancer sequence, to gene expression patterns (4). Murine limbs display two successive phases of gene expression of the HoxD and HoxA gene clusters.…”

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confidence: 99%

Deep conservation of wrist and digit enhancers in fish

Gehrke

Schneider

Calle‐Mustienes

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

120

152

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There is no obvious morphological counterpart of the autopod (wrist/ankle and digits) in living fishes. Comparative molecular data may provide insight into understanding both the homology of elements and the evolutionary developmental mechanisms behind the fin to limb transition. In mouse limbs the autopod is built by a "late" phase of Hoxd and Hoxa gene expression, orchestrated by a set of enhancers located at the 5′ end of each cluster. Despite a detailed mechanistic understanding of mouse limb development, interpretation of Hox expression patterns and their regulation in fish has spawned multiple hypotheses as to the origin and function of "autopod" enhancers throughout evolution. Using phylogenetic footprinting, epigenetic profiling, and transgenic reporters, we have identified and functionally characterized hoxD and hoxA enhancers in the genomes of zebrafish and the spotted gar, Lepisosteus oculatus, a fish lacking the whole genome duplication of teleosts. Gar and zebrafish "autopod" enhancers drive expression in the distal portion of developing zebrafish pectoral fins, and respond to the same functional cues as their murine orthologs. Moreover, gar enhancers drive reporter gene expression in both the wrist and digits of mouse embryos in patterns that are nearly indistinguishable from their murine counterparts. These functional genomic data support the hypothesis that the distal radials of bony fish are homologous to the wrist and/or digits of tetrapods.he origin of novel features is a key question in evolutionary biology, and the autopod-wrists, fingers, ankles, and toesis a hallmark example (1). Although paleontological data, such as that from the Devonian lobe fin Tiktaalik roseae, reveal a sequence of changes in the elaboration of the bony elements of fins into limbs (2), in living taxa there is a lack of obvious homology between the wrist and digits of tetrapod limbs and the pectoral fin skeleton of extant fish (3). Tetrapod forelimbs are generally composed of a series of long bones (upper arm and forearm), followed by small nodular bones (wrist), and ending in another group of long bones (digits). Ray-finned (Actinopterygian) pectoral fins are diverse but are usually composed of a series of long proximal radials, followed by a set of smaller distal radials. The open question remains: do extant fish have the equivalent of wrists or digits?The molecular mechanisms governing the development of mammalian limbs have been approached in mouse models through multiple levels of analysis, from chromatin dynamics, to enhancer sequence, to gene expression patterns (4). Murine limbs display two successive phases of gene expression of the HoxD and HoxA gene clusters. The initial or "early" phase of expression begins with members at the 3′ end of the clusters being expressed broadly, and members at the 5′ end of the cluster being activated in an increasingly restricted number of cells (5). This "early" phase of Hox expression is associated with the development of the upper arm (stylopod) and forearm (zeugopod). The ...

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“…Studies of the mouse HoxD cluster have provided insights into the global regulation of its nine consecutive genes during limb development, including the presence of multiple regulatory sequences spanning a 2-megabase large DNA interval (18). Recently, this gene cluster, similar to its HoxA relative (14,15), was shown to reside at a boundary between two TADs (located ca.…”

mentioning

confidence: 99%

Nanoscale spatial organization of the HoxD gene cluster in distinct transcriptional states

Fabre

Benke

Joye

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Chromatin condensation plays an important role in the regulation of gene expression. Recently, it was shown that the transcriptional activation of Hoxd genes during vertebrate digit development involves modifications in 3D interactions within and around the HoxD gene cluster. This reorganization follows a global transition from one set of regulatory contacts to another, between two topologically associating domains (TADs) located on either side of the HoxD locus. Here, we use 3D DNA FISH to assess the spatial organization of chromatin at and around the HoxD gene cluster and report that although the two TADs are tightly associated, they appear as spatially distinct units. We measured the relative position of genes within the cluster and found that they segregate over long distances, suggesting that a physical elongation of the HoxD cluster can occur. We analyzed this possibility by super-resolution imaging (STORM) and found that tissues with distinct transcriptional activity exhibit differing degrees of elongation. We also observed that the morphological change of the HoxD cluster in developing digits is associated with its position at the boundary between the two TADs. Such variations in the fine-scale architecture of the gene cluster suggest causal links among its spatial configuration, transcriptional activation, and the flanking chromatin context. DNA FISH | super-resolution microscopy | limb development | topologically associating domains | HoxD

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Chromatin organization and global regulation ofHoxgene clusters

Cited by 70 publications

References 93 publications

Reconstructed cell fate–regulatory programs in stem cells reveal hierarchies and key factors of neurogenesis

Reconstructed cell fate–regulatory programs in stem cells reveal hierarchies and key factors of neurogenesis

Deep conservation of wrist and digit enhancers in fish

Nanoscale spatial organization of the HoxD gene cluster in distinct transcriptional states

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