AMPK phosphorylates LMX1b to regulate a brainstem neurogenic network important for control of breathing in neonatal mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1198987 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31759257.fastq.gz | Fastqsanger.gz | |||
| SRR31759258.fastq.gz | Fastqsanger.gz | |||
| SRR31759259.fastq.gz | Fastqsanger.gz | |||
| SRR31759260.fastq.gz | Fastqsanger.gz | |||
| SRR31759261.fastq.gz | Fastqsanger.gz |
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Project description:Lmx1b is a homeodomain transcription factor responsible for limb dorsalization. Despite striking double-ventral (loss-of-function) and double-dorsal (gain-of-function) limb phenotypes, no direct downstream gene targets in the limb have been confirmed. To determine direct targets of Lmx1b during limb dorsalization (E12.5), we performed chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq). Nearly 84% (n=617) of the Lmx1b-bound genomic fragments or intervals (LBIs) identified by two Lmx1b-ChIP-seqs overlap with chromatin regulatory marks indicative of potential cis-regulatory modules (PCRMs). In addition, 73 LBIs mapped to known cis-regulatory modules (CRMs) active during limb development. We compared Lmx1b-bound PCRMs to genes differentially expressed by Lmx1b at E12.5 and found 292 PCRMs within 1 Mb of 254 Lmx1b-regulated genes. Gene ontology analysis of these associated genes suggests that Lmx1b mediates dorsalization through the regulation of extracellular matrix production, bone/joint formation, axonal guidance, vascular development, cell proliferation and cell movement. We validated the functional activity of 2 PCRMs associated to Lmx1b-regulated genes, demonstrating activity and overlap with the associated gene during limb development. This is the first report to describe the genome-wide distribution of Lmx1b binding during limb development, directly linking Lmx1b to targets that accomplish limb dorsalization.
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Project description:A control vs. genetic knockout experiment aimed at determining what RNAs are upregulated or downregulated in e11.5 mouse proximal limb tissue lacking the Lmx1b gene. Because Lmx1b is required for dorsal-ventral patterning of the limb, this screen gives insight into what putative downstream targets of Lmx1b contribute to dorsal-ventral patterning. Keywords: Genetic allele comparison
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Project description:Pathogenic coding mutations are prevalent in human neuronal transcription factors (TFs) but how they disrupt development is poorly understood. Lmx1b is a master transcriptional regulator of postmitotic serotonin (5-HT) neuron development; over two hundred pathogenic heterozygous mutations have been discovered in human LMX1B, yet their impact on brain development has not been investigated. Here, we developed mouse models with different LMX1B DNA-binding missense mutations. Missense heterozygosity effected highly specific deficits in the postnatal maturation of forebrain serotonin axon arbors, primarily in the hippocampus and motor cortex, which was associated with spatial memory defects. Digital Genomic Footprinting (DGF) revealed that missense heterozygosity caused complete loss of Lmx1b motif protection and chromatin accessibility at sites enriched for a distal active enhancer/active promoter histone signature and homeodomain binding motifs; at other bound Lmx1b motifs, varying levels of losses, gains or unchanged accessibility were found. The spectrum of footprint changes was strongly associated with synapse and axon genes. Lmx1b missense heterozygosity further caused wide disruption of Lmx1b-dependent regulatory networks comprising diverse TFs. These findings suggest Lmx1b missense heterozygosity forces complex dominant negative-like and hypomorphic perturbations on serotonergic regulatory element TF binding and accessibility. Our work illustrates the power of DGF for gaining insight into how TF missense mutations disrupt regulatory networks within neuronal epigenomes.
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Project description:LMX1B is a LIM-homeodomain transcription factor essential for development. Putative LMX1B target genes have been identified through mouse gene targeting studies; however, in the absence of in vivo molecular characterization of their regulation, their identity as direct LMX1B targets remains hypothetical. We describe here the first molecular characterization of LMX1B target gene regulation. A tetracycline-inducible expression system and microarray analysis showed that a subset of NF-kappa B target genes, including IL-6 and IL-8 are upregulated in LMX1B-expressing HeLa cells. Chromatin immunoprecipitation assays revealed that LMX1B binds to the proximal promoter region of IL-6 and IL-8 in vivo, in the vicinity of the characterized kappa B site, and that LMX1B recruitment correlates with an increased NF-kappa B DNA association. Inhibition of NF-kappa B activity by short interfering RNA-mediated knock-down of p65 impairs LMX1B-dependent induction of NF-kappa B target genes, while activation of NF-kappa B activity by TNF-alpha results in a synergistic induction of these genes by LMX1B. IL-6 promoter-driven reporter assays showed that the kappa B site and an adjacent putative LMX1B binding motif are both involved in LMX1B-mediated transcription. Expression of a number of NF-kappa B target genes is affected in the kidney of Lmx1b-/- knock-out mice, thus supporting the biological relevance of the data obtained in the human cell line. Together, these data demonstrate for the first time that LMX1B directly regulates transcription of a subset of NF-kappa B target genes in cooperation with nuclear p50/p65 NF-kappa B. Human subset (GSM303547-GSM303550): Two biological replicates of non-expressing HtTA-LMX1B cells (grown in doxycycline-containing medium) and of LMX1B-expressing HtTA-LMX1B cells (grown for 4 days in doxycycline-free medium) were processed for gene expression array analyses using an Affymetrix platform. Mouse subset (GSM304379-GSM304384): Three kidney samples from newborn wild-type mice and from newborn Lmx1b-/- knock-out mice were processed for gene expression array analyses using an Agilent platform.
2008-12-03 | E-GEOD-12008 | biostudies-arrayexpress
Project description:A control vs. genetic knockout experiment aimed at determining what RNAs are upregulated or downregulated in E13.5 mouse limb tissue lacking the Lmx1b gene. Because LMX1B is required for dorsal-ventral patterning of the limb, this screen gives insight into what putative downstream targets of Lmx1b contribute to dorsal-ventral patterning. The forelimb or hindlimb of wild-type controls or Lmx1b loss-of-function mutants was used for RNA extraction. Each array was hybridized with cDNAs of an individual limb.
2010-07-30 | E-GEOD-21446 | biostudies-arrayexpress
Project description:A control vs. genetic knockout experiment aimed at determining what RNAs are upregulated or downregulated in E13.5 mouse limb tissue lacking the Lmx1b gene. Because LMX1B is required for dorsal-ventral patterning of the limb, this screen gives insight into what putative downstream targets of Lmx1b contribute to dorsal-ventral patterning.
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Project description:Mammalian digit tip regeneration is linked to the presence of nail tissue, but a nail-explicit model is missing. Here, we report that nail-less double-ventral digits of ΔLARM1/2 mutants that lack limb-specific Lmx1b enhancers, fail to regenerate. To separate the nail’s effect from the lack of DV polarity, we also interrogate double-dorsal double-nail digits and show that they regenerate. Thus, DV polarity is not a prerequisite for regeneration and the nail requirement is supported. Transcriptomic comparison between wild-type and non-regenerative ΔLARM1/2 mutant blastemas reveals differential up-regulation of vascularization and connective tissue functional signatures in wild-type versus upregulation of inflammation in the mutant. These results, together with the finding of Lmx1b expression in the postnatal dorsal dermis underneath the nail and uniformly in the regenerative blastema opens the possibility of additional Lmx1b roles in the progression of digit tip regeneration, in addition to the indirect effect of mediating the formation of the nail.
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Project description:LMX1B is a LIM-homeodomain transcription factor essential for development. Putative LMX1B target genes have been identified through mouse gene targeting studies; however, in the absence of in vivo molecular characterization of their regulation, their identity as direct LMX1B targets remains hypothetical. We describe here the first molecular characterization of LMX1B target gene regulation. A tetracycline-inducible expression system and microarray analysis showed that a subset of NF-kappa B target genes, including IL-6 and IL-8 are upregulated in LMX1B-expressing HeLa cells. Chromatin immunoprecipitation assays revealed that LMX1B binds to the proximal promoter region of IL-6 and IL-8 in vivo, in the vicinity of the characterized kappa B site, and that LMX1B recruitment correlates with an increased NF-kappa B DNA association. Inhibition of NF-kappa B activity by short interfering RNA-mediated knock-down of p65 impairs LMX1B-dependent induction of NF-kappa B target genes, while activation of NF-kappa B activity by TNF-alpha results in a synergistic induction of these genes by LMX1B. IL-6 promoter-driven reporter assays showed that the kappa B site and an adjacent putative LMX1B binding motif are both involved in LMX1B-mediated transcription. Expression of a number of NF-kappa B target genes is affected in the kidney of Lmx1b-/- knock-out mice, thus supporting the biological relevance of the data obtained in the human cell line. Together, these data demonstrate for the first time that LMX1B directly regulates transcription of a subset of NF-kappa B target genes in cooperation with nuclear p50/p65 NF-kappa B.
2008-12-04 | GSE12008 | GEO