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Rapid clearance of PcG histone modifications from Hox genes anticipates motor neuron differentiation: ChIP-chip

ABSTRACT: [original Title] Rapid and synchronous clearance of PcG histone modifications from Hox genes anticipates motor neuron differentiation. Hox genes are expressed in patterns that are spatially and temporally collinear with their chromosomal organization. This feature is an evolutionarily conserved hallmark of embryonic development, and in vertebrates it is critical, among others, for the specification of motor neuron subtypes and the wiring of sensory-motor circuits. We show here that the differentiation of motor neurons from stem cells is accompanied by a synchronous, domain-wide clearance of “repressive” Polycomb (PcG)-dependent histone methylation from Hox gene chromatin domains. These findings argue against the idea, advanced recently, that the collinear dynamics of Hox gene expression invariably reflects the progressive clearance of repressive chromatin modifications. The rapid establishment of stable chromatin domains in response to a transient patterning signal likely serves as a molecular correlate of enduring rostro-caudal neural identity, which underlies the specification of postmitotic motor neuron subtype diversity and neuronal circuit assembly.

ORGANISM(S): Mus musculus

PROVIDER: GSE19447 | GEO | 2013/07/04

SECONDARY ACCESSION(S): PRJNA123693

REPOSITORIES: GEO

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Rapid clearance of PcG histone modifications from Hox genes anticipates motor neuron differentiation: ChIP-chip

Project description:[original Title] Rapid and synchronous clearance of PcG histone modifications from Hox genes anticipates motor neuron differentiation. Hox genes are expressed in patterns that are spatially and temporally collinear with their chromosomal organization. This feature is an evolutionarily conserved hallmark of embryonic development, and in vertebrates it is critical, among others, for the specification of motor neuron subtypes and the wiring of sensory-motor circuits. We show here that the differentiation of motor neurons from stem cells is accompanied by a synchronous, domain-wide clearance of M-bM-^@M-^\repressiveM-bM-^@M-^] Polycomb (PcG)-dependent histone methylation from Hox gene chromatin domains. These findings argue against the idea, advanced recently, that the collinear dynamics of Hox gene expression invariably reflects the progressive clearance of repressive chromatin modifications. The rapid establishment of stable chromatin domains in response to a transient patterning signal likely serves as a molecular correlate of enduring rostro-caudal neural identity, which underlies the specification of postmitotic motor neuron subtype diversity and neuronal circuit assembly. The differentiation of ventral motor neurons is induced by treating embryonic stem cell cultures with retinoic acid and hedgehog agonist. Here, ChIP-chip using a custom Agilent array is used to profile the occupancy of H3K27me3, H3K4me3, and H3K79me2 at various defined stages during the differentiation process.

2013-07-04 | E-GEOD-19447 | biostudies-arrayexpress

Project description:Rapid and synchronous clearance of PcG histone modifications from Hox genes anticipates motor neuron differentiation

| PRJNA120309 | ENA

Mus musculus

Project description:Rapid clearance of PcG histone modifications from Hox genes anticipates motor neuron differentiation: ChIP-chip

| PRJNA123693 | ENA

Induced Cdx2 binding in progenitor motor neurons and its effect on H3K27me3 chromatin domains [Affymetrix]

Project description:We aim to understand the role that Cdx2 plays in specifying the rostro-caudal identity of differentiating motor neurons. We find that expressing Cdx2 in combination with FGF signaling is sufficient to produce motor neurons with a more caudal identity. ChIP-seq analysis of Cdx2 finds that it binds extensively throughout the Hox regions in progenitor motor neurons. Analysis of polycomb-associated chromatin over Hox regions in the subsequently generated motor neurons finds that Cdx2 binding corresponds to chromatin domains encompassing de-repressed caudal Hox genes. These results suggest a direct role for Cdx2 in specifying caudal motor neuron identity. Expression studies: Affymetrix arrays are used to profile gene expression in ES cells, RA/Hh-derived Day 5 motor neurons, and RA/Hh-derived motor neurons that have also been exposed to Dox (to activate iCdx2) and FGF.

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Project description:To dissect the significance underlying the delay between Hox transcription and translation, we profiled global Hox gene expression using an in vitro ESC-derived motor neuron differentiation system

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Induced Cdx2 binding in progenitor motor neurons and its effect on H3K27me3 chromatin domains [ChIP-Seq]

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Induced Cdx2 binding in progenitor motor neurons and its effect on H3K27me3 chromatin domains [Affymetrix]

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Dynamic extrinsic pacing of the HOX clock in human axial progenitors control motor neuron subtype specification

Project description:Dynamic extrinsic pacing of the HOX clock in human axial progenitors control motor neuron subtype specification

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Dynamic extrinsic pacing of the HOX clock in human axial progenitors control motor neuron subtype specification

Project description:Rostro-caudal patterning of vertebrates depends on the temporally progressive activation of HOX genes within axial stem cells that fuel axial embryo elongation. Whether HOX genes sequential activation, the “HOX clock”, is paced by intrinsic chromatin-based timing mechanisms or by temporal changes in extrinsic cues remains unclear. Here, we studied HOX clock pacing in human pluripotent stem cells differentiating into spinal cord motor neuron subtypes which are progenies of axial progenitors. We show that the progressive activation of caudal HOX genes is controlled by a dynamic increase in FGF signaling. Blocking FGF pathway stalled induction of HOX genes, while precocious increase in FGF alone, or with GDF11 ligand, accelerated the HOX clock. Cells differentiated under accelerated HOX induction generated appropriate posterior motor neuron subtypes found along the human embryonic spinal cord. The HOX clock is thus dynamically paced by exposure parameters to secreted cues. Its manipulation by extrinsic factors alleviates temporal requirements to provide unprecedented synchronized access to human cells of multiple, defined, rostro-caudal identities for basic and translational applications.

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Spinal motor neuron development and metabolism are transcriptionally regulated by Nuclear Factor IA [RNA-Seq]

Project description:Neural circuits governing complex motor behaviors in vertebrates rely on the proper development of motor neurons and their precise targeting of limb muscles. Transcription factors are essential for motor neuron development, regulating their specification, migration, and axonal targeting. While transcriptional regulation of the early stages of motor neuron specification is well-established, much less is known about the role of transcription factors in the later stages of maturation and terminal arborization. Defining the molecular mechanisms of these later stages is critical for elucidating how motor circuits are constructed. Here, we demonstrate that the transcription factor Nuclear Factor-IA (NFIA) is required for motor neuron positioning, axonal branching, and neuromuscular junction formation. Moreover, we find that NFIA is required for proper mitochondrial function and ATP production, providing a new and important link between transcription factors and metabolism during motor neuron development. Together, these findings underscore the critical role of NFIA in instructing the assembly of spinal circuits for movement.

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